16S rRNA next generation sequencing analysis shows bacteria in Alzheimer's Post-Mortem Brain

Frontiers in Aging Neuroscience

Volumn 9, Issue JUN, 2017, Pages

  Emery, David C ^a   Shoemark, Deborah K ^a   Batstone, Tom E ^a   Waterfall, Christy M ^a   Coghill, Jane A ^a   Cerajewska, Tanya L ^b   Davies, Maria ^b   West, Nicola X ^b   Allen, Shelley J ^a  

^a UNIVERSITY OF BRISTOL   (United Kingdom)

^b Oral Nanoscience School of Oral and Dental Sciences   (United Kingdom)

Author keywords

16S rRNA; Alzheimer's disease (AD); Bacteria; Human microbiome; Next generation sequencing (NGS)

Indexed keywords

FORMALDEHYDE; RNA 16S;

ACTINOBACTERIA; ADULT; AGED; ALZHEIMER DISEASE; ARTICLE; AUTOPSY; BACTERIAL LOAD; BACTERIUM IDENTIFICATION; BRAIN TISSUE; CLINICAL ARTICLE; COHORT ANALYSIS; COMPARATIVE STUDY; CONTROLLED STUDY; FEMALE; FIRMICUTES; FROZEN SECTION; FUSOBACTERIA; HUMAN; HUMAN TISSUE; IMMUNOHISTOCHEMISTRY; MALE; MIDDLE AGED; NEUROPATHOLOGY; NEXT GENERATION SEQUENCING; NONHUMAN; PILOT STUDY; POLYMERASE CHAIN REACTION; PROTEOBACTERIA; TISSUE FIXATION; VERY ELDERLY;

EID: 85020882000     PISSN: None     EISSN: 16634365     Source Type: Journal    
DOI: 10.3389/fnagi.2017.00195     Document Type: Article

References (110)

1. Achermann, Y., Goldstein, E. J., Coenye, T., and Shirtliff, M. E. (2014). Propionibacterium acnes: from commensal to opportunistic biofilm-associated implant pathogen. Clin. Microbiol. Rev. 27, 419-440. doi: 10.1128/CMR.00092-13
2. Aizenstein, H. J., Nebes, R. D., Saxton, J. A., Price, J. C., Mathis, C. A., Tsopelas, N. D., et al. (2008). Frequent amyloid deposition without significant cognitive impairment among the elderly. Arch. Neurol. 65, 1509-1517. doi: 10.1001/archneur.65.11.1509
3. Akiyama, H., Arai, T., Kondo, H., Tanno, E., Haga, C., and Ikeda, K. (2000a). Cell mediators of inflammation in the Alzheimer disease brain. Alzheimer Dis. Assoc. Disord. 14, S47-S53. doi: 10.1097/00002093-200000001-00008
4. Akiyama, H., Barger, S., Barnum, S., Bradt, B., Bauer, J., Cole, G. M., et al. (2000b). Inflammation and Alzheimer's disease. Neurobiol. Aging 21, 383-421. doi: 10.1016/S0197-4580(00)00124-X
5. American Psychiatric Association. (2000). Diagnostic and Statistical Manual of Mental Disorders. DSM-IV-TR. 4th Edn. Washington, DC: American Psychiatric Association
6. Arumugam, M., Raes, J., Pelletier, E., Le Paslier, D., Yamada, T., Mende, D. R., et al. (2011). Enterotypes of the human gut microbiome. Nature 473, 174-180. doi: 10.1038/nature09944
7. Balin, B. J., Little, C. S., Hammond, C. J., Appelt, D. M., Whittum-Hudson, J. A., Gerard, H. C., et al. (2008). Chlamydophila pneumoniae and the etiology of late-onset Alzheimer's disease. J. Alzheimers Dis. 13, 371-380. doi: 10.3233/jad-2008-13403
8. Bateman, R. J., Xiong, C., Benzinger, T. L., Fagan, A. M., Goate, A., Fox, N. C., et al. (2012). Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N. Engl. J. Med. 367, 795-804. doi: 10.1056/NEJMoa1202753
9. Bell, R. D. (2012). The imbalance of vascular molecules in Alzheimer's disease. J. Alzheimers Dis. 32, 699-709. doi: 10.3233/JAD-2012-121060
10. Bell, R. D., Winkler, E. A., Singh, I., Sagare, A. P., Deane, R., Wu, Z., et al. (2012). Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature 485, 512-516. doi: 10.1038/nature11087
11. Bertram, L., and Tanzi, R. E. (2009). Genome-wide association studies in Alzheimer's disease. Hum. Mol. Genet. 18, R137-R145. doi: 10.1093/hmg/ddp406
12. Bhatia, A. M., Maisonneuve, J.-F., and Persing, D. H. (2004). 'Propionobacterium acnes and chronic diseases,' in The Infectious Etiology of Chronic Diseases: Defining the Relationship, Enhancing the Research, and Mitigating the Effects, eds S. L. Knobler, S. O'Connor, S. M. Lemon and M. Najafi, (Seattle, WA: Corixa Corporation), 74-80
13. Bolger, A. M., Lohse, M., and Usadel, B. (2014). Trimmomatic: a flexible trimmer for illumina sequence data. Bioinformatics 30, 2114-2120. doi: 10.1093/bioinformatics/btu170
14. Böttger, E. C. (1989). Rapid determination of bacterial ribosomal RNA sequences by direct sequencing of enzymatically amplified DNA. FEMS Microbiol. Lett. 53, 171-176. doi: 10.1016/0378-1097(89)90386-8
15. Branton, W. G., Ellestad, K. K., Maingat, F., Wheatley, B. M., Rud, E., Warren, R. L., et al. (2013). Brain microbial populations in HIV/AIDS: a-proteobacteria predominate independent of host immune status. PLoS One 8:e54673. doi: 10.1371/journal.pone.0054673
16. Branton, W. G., Lu, J. Q., Surette, G., Holt, R. A., Lind, J., Laman, J. D., et al. (2016). Brain microbiota disruption within inflammatory demyelinating lesions in multiple sclerosis. Sci. Rep. 6:37344. doi: 10.1038/srep37344
17. Buchanan, A. M., Davis, D. C., Pedersen, N. C., and Beaman, B. L. (1982). Recovery of microorganisms from synovial and pleural fluids of animals using hyperosmolar media. Vet. Microbiol. 7, 19-33. doi: 10.1016/0378-1135(82)90003-7
18. Caporaso, J. G., Bittinger, K., Bushman, F. D., DeSantis, T. Z., Andersen, G. L., and Knight, R. (2010a). Pynast: a flexible tool for aligning sequences to a template alignment. Bioinformatics 26, 266-267. doi: 10.1093/bioinformatics/btp636
19. Caporaso, J. G., Kuczynski, J., Stombaugh, J., Bittinger, K., Bushman, F. D., Costello, E. K., et al. (2010b). Qiime allows analysis of high-throughput community sequencing data. Nat. Methods 7, 335-336. doi: 10.1038/nmeth.f.303
20. Castelo-Branco, C., and Soveral, I. (2014). The immune system and aging: a review. Gynecol. Endocrinol. 30, 16-22. doi: 10.3109/09513590.2013.852531
21. Cerajewska, T. L., Davies, M., and West, N. X. (2015). Periodontitis: a potential risk factor for Alzheimer's disease. Br. Dent. J. 218, 29-34. doi: 10.1038/sj.bdj.2014.1137
22. Chakravorty, S., Helb, D., Burday, M., Connell, N., and Alland, D. (2007). A detailed analysis of 16s ribosomal RNA gene segments for the diagnosis of pathogenic bacteria. J. Microbiol. Methods 69, 330-339. doi: 10.1016/j.mimet.2007.02.005
23. Chen, S., Averett, N. T., Manelli, A., LaDu, M. J., May, W., and Ard, M. D. (2005). Isoform-specific effects of apolipoprotein E on secretion of inflammatory mediators in adult rat microglia. J. Alzheimers Dis. 7, 25-35. doi: 10.3233/JAD-2005-7104
24. Chen, S. G., Stribinskis, V., Rane, M. J., Demuth, D. R., Gozal, E., Roberts, A. M., et al. (2016). Exposure to the functional bacterial amyloid protein curli enhances alpha-synuclein aggregation in aged fischer 344 rats and Caenorhabditis elegans. Sci. Rep. 6:34477. doi: 10.1038/srep34477
25. Clarridge, J. E. III. (2004). Impact of 16S rRNA gene sequence analysis for identification of bacteria on clinical microbiology and infectious diseases. Clin. Microbiol. Rev. 17, 840-862. doi: 10.1128/cmr.17.4.840-862.2004
26. DeSantis, T. Z., Hugenholtz, P., Larsen, N., Rojas, M., Brodie, E. L., Keller, K., et al. (2006). Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with arb. Appl. Environ. Microbiol. 72, 5069-5072. doi: 10.1128/aem.03006-05
27. Dewhirst, F. E., Chen, T., Izard, J., Paster, B. J., Tanner, A. C., Yu, W. H., et al. (2010). The human oral microbiome. J. Bacteriol. 192, 5002-5017. doi: 10.1128/JB.00542-10
28. Edgar, R. C. (2010). Search and clustering orders of magnitude faster than blast. Bioinformatics 26, 2460-2461. doi: 10.1093/bioinformatics/btq461
29. Edgar, R. C., Haas, B. J., Clemente, J. C., Quince, C., and Knight, R. (2011). Uchime improves sensitivity and speed of chimera detection. Bioinformatics 27, 2194-2200. doi: 10.1093/bioinformatics/btr381
30. Esparza, T. J., Zhao, H., Cirrito, J. R., Cairns, N. J., Bateman, R. J., Holtzman, D. M., et al. (2013). Amyloid-beta oligomerization in Alzheimer dementia vs. high-pathology controls. Ann. Neurol. 73, 104-119. doi: 10.1002/ana.23748
31. Fournier, P. E., Dubourg, G., and Raoult, D. (2014). Clinical detection and characterization of bacterial pathogens in the genomics era. Genome Med. 6:114. doi: 10.1186/s13073-014-0114-2
32. Fujii, R., Saito, Y., Tokura, Y., Nakagawa, K. I., Okuda, K., and Ishihara, K. (2009). Characterization of bacterial flora in persistent apical periodontitis lesions. Oral Microbiol. Immunol. 24, 502-505. doi: 10.1111/j.1399-302X.2009.00534.x
33. Gatz, M., Mortimer, J. A., Fratiglioni, L., Johansson, B., Berg, S., Reynolds, C. A., et al. (2006). Potentially modifiable risk factors for dementia in identical twins. Alzheimers Dement. 2, 110-117. doi: 10.1016/j.jalz.2006.01.002
34. Gieffers, J., Reusche, E., Solbach, W., and Maass, M. (2000). Failure to detect chlamydia pneumoniae in brain sections of Alzheimer's disease patients. J. Clin. Microbiol. 38, 881-882
35. Guerreiro, R., and Hardy, J. (2014). Genetics of Alzheimer's disease. Neurotherapeutics 11, 732-737. doi: 10.1007/s13311-014-0295-9
36. Guo, L., Ladu, M. J., and Van Eldik, L. J. (2004). A dual role for apolipoprotein e in neuroinflammation: anti-and pro-inflammatory activity. J. Mol. Neurosci. 23, 205-212. doi: 10.1385/jmn:23:3:205
37. Harris, S. A., and Harris, E. A. (2015). Herpes simplex virus type 1 and other pathogens are key causative. J. Alzheimers Dis. 48, 319-353. doi: 10.3233/JAD-142853
38. Heneka, M. T., Carson, M. J., El Khoury, J., Landreth, G. E., Brosseron, F., Feinstein, D. L., et al. (2015a). Neuroinflammation in Alzheimer's disease. Lancet Neurol. 14, 388-405. doi: 10.1016/S1474-4422(15)70016-5
39. Heneka, M. T., Golenbock, D. T., and Latz, E. (2015b). Innate immunity in Alzheimer's disease. Nat. Immunol. 16, 229-236. doi: 10.1038/ni.3102
40. Hill, J. M., Clement, C., Pogue, A. I., Bhattacharjee, S., Zhao, Y., and Lukiw, W. J. (2014). Pathogenic microbes, the microbiome, and Alzheimer's disease (AD). Front. Aging Neurosci. 6:127. doi: 10.3389/fnagi.2014.00127
41. Holmes, C., Cunningham, C., Zotova, E., Woolford, J., Dean, C., Kerr, S., et al. (2009). Systemic inflammation and disease progression in Alzheimer disease. Neurology 73, 768-774. doi: 10.1212/WNL.0b013e3181b6bb95
42. Hulette, C. M., Welsh-Bohmer, K. A., Murray, M. G., Saunders, A. M., Mash, D. C., and McIntyre, L. M. (1998). Neuropathological and neuropsychological changes in 'normal' aging: evidence for preclinical Alzheimer disease in cognitively normal individuals. J. Neuropathol. Exp. Neurol. 57, 1168-1174. doi: 10.1097/00005072-199812000-00009
43. Human Microbiome Project Consortium. (2012). Structure, function and diversity of the healthy human microbiome. Nature 486, 207-214. doi: 10.1038/nature11234
44. Itzhaki, R. F., Lathe, R., Balin, B. J., Ball, M. J., Bearer, E. L., Braak, H., et al. (2016). Microbes and Alzheimer's disease. J. Alzheimers Dis. 51, 979-984. doi: 10.3233/JAD-160152
45. Kamer, A. R., Craig, R. G., Pirraglia, E., Dasanayake, A. P., Norman, R. G., Boylan, R. J., et al. (2009). TNF-a and antibodies to periodontal bacteria discriminate between Alzheimer's disease patients and normal subjects. J. Neuroimmunol. 216, 92-97. doi: 10.1016/j.jneuroim.2009.08.013
46. Karlsson, F. H., Tremaroli, V., Nookaew, I., Bergstrom, G., Behre, C. J., Fagerberg, B., et al. (2013). Gut metagenome in european women with normal, impaired and diabetic glucose control. Nature 498, 99-103. doi: 10.1038/nature12198
47. Katzman, R., Terry, R., DeTeresa, R., Brown, T., Davies, P., Fuld, P., et al. (1988). Clinical, pathological, and neurochemical changes in dementia: a subgroup with preserved mental status and numerous neocortical plaques. Ann. Neurol. 23, 138-144. doi: 10.1002/ana.410230206
48. Kornhuber, H. H. (1996). Propionibacterium acnes in the cortex of patients with Alzheimer's disease. Eur. Arch. Psychiatry Clin. Neurosci. 246, 108-109. doi: 10.1007/bf02274902
49. Kountouras, J., Deretzi, G., Gavalas, E., Zavos, C., Polyzos, S. A., Kazakos, E., et al. (2014). A proposed role of human defensins in helicobacter pylori-related neurodegenerative disorders. Med. Hypotheses 82, 368-373. doi: 10.1016/j.mehy.2013.12.025
50. Kumar, D. K., Choi, S. H., Washicosky, K. J., Eimer, W. A., Tucker, S., Ghofrani, J., et al. (2016). Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer's disease. Sci. Transl. Med. 8:340ra372. doi: 10.1126/scitranslmed.aaf1059
51. LaDu, M. J., Shah, J. A., Reardon, C. A., Getz, G. S., Bu, G., Hu, J., et al. (2001). Apolipoprotein E and apolipoprotein E receptors modulate Aβ-induced glial neuroinflammatory responses. Neurochem. Int. 39, 427-434. doi: 10.1016/s0197-0186(01)00050-x
52. Laurence, M., Hatzis, C., and Brash, D. E. (2014). Common contaminants in next-generation sequencing that hinder discovery of low-abundance microbes. PLoS One 9:e97876. doi: 10.1371/journal.pone.0097876
53. Ley, R. E., Bäckhed, F., Turnbaugh, P., Lozupone, C. A., Knight, R. D., and Gordon, J. I. (2005). Obesity alters gut microbial ecology. Proc. Natl. Acad. Sci. U S A 102, 11070-11075. doi: 10.1073/pnas.0504978102
54. Licastro, F., Candore, G., Lio, D., Porcellini, E., Colonna-Romano, G., Franceschi, C., et al. (2005). Innate immunity and inflammation in ageing: a key for understanding age-related diseases. Immun. Ageing 2:8. doi: 10.1186/1742-4933-2-8
55. Lozupone, C., and Knight, R. (2005). Unifrac: a new phylogenetic method for comparing microbial communities. Appl. Environ. Microbiol. 71, 8228-8235. doi: 10.1128/aem.71.12.8228-8235.2005
56. Lusk, R. W. (2014). Diverse and widespread contamination evident in the unmapped depths of high throughput sequencing data. PLoS One 9:e110808. doi: 10.1371/journal.pone.0110808
57. Lynch, M. A. (2010). Age-related neuroinflammatory changes negatively impact on neuronal function. Front. Aging Neurosci. 1:6. doi: 10.3389/neuro.24.006.2009
58. MacDonald, A. B., and Miranda, J. M. (1987). Concurrent neocortical borreliosis and Alzheimer's disease. Hum. Pathol. 18, 759-761. doi: 10.1016/s0046-8177(87)80252-6
59. Malik, M., Parikh, I., Vasquez, J. B., Smith, C., Tai, L., Bu, G., et al. (2015). Genetics ignite focus on microglial inflammation in Alzheimer's disease. Mol. Neurodegener. 10:52. doi: 10.1186/s13024-015-0048-1
60. Mawanda, F., and Wallace, R. (2013). Can infections cause Alzheimer's disease? Epidemiol. Rev. 35, 161-180. doi: 10.1093/epirev/mxs007
61. McDowell, A., Patrick, S., Eishi, Y., Lambert, P., and Eady, A. (2013). Propionibacterium acnes in human health and disease. Biomed Res. Int. 2013:493564. doi: 10.1155/2013/493564
62. Merril, C. R. (2013). Is sporadic Alzheimer's disease associated with diphtheria toxin? J. Alzheimers Dis. 34, 595-600. doi: 10.3233/JAD-121948
63. Miklossy, J. (2011). Emerging roles of pathogens in Alzheimer disease. Expert Rev. Mol. Med. 13:e30. doi: 10.1017/S1462399411002006
64. Miklossy, J. (2015). Historic evidence to support a causal relationship between spirochetal infections and Alzheimer's disease. Front. Aging Neurosci. 7:46. doi: 10.3389/fnagi.2015.00046
65. Miklossy, J., Kis, A., Radenovic, A., Miller, L., Forro, L., Martins, R., et al. (2006). Beta-amyloid deposition and Alzheimer's type changes induced by borrelia spirochetes. Neurobiol. Aging 27, 228-236. doi: 10.1016/j.neurobiolaging.2005.01.018
66. Miklossy, J., and McGeer, P. L. (2016). Common mechanisms involved in Alzheimer's disease and type 2 diabetes: a key role of chronic bacterial infection and inflammation. Aging (Albany NY) 8, 575-588. doi: 10.18632/aging.100921
67. Minter, M. R., Zhang, C., Leone, V., Ringus, D. L., Zhang, X., Oyler-Castrillo, P., et al. (2016). Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer's disease. Sci. Rep. 6:30028. doi: 10.1038/srep30028
68. Mollerup, S., Friss-Nielsen, J., Vinner, L., Hansen, T. A., Richter, S. R., Fridholm, H., et al. (2016). Propionibacterium acnes: disease-causing agent or common contaminant? Detection in diverse patient samples by next generation sequencing. J. Clin. Microbiol. 54, 980-987. doi: 10.1128/JCM.02723-15
69. Mori, H., Maruyama, F., Kato, H., Toyoda, A., Dozono, A., Ohtsubo, Y., et al. (2014). Design and experimental application of a novel non-degenerate universal primer set that amplifies prokaryotic 16s rRNA genes with a low possibility to amplify eukaryotic rRNA genes. DNA Res. 21, 217-227. doi: 10.1093/dnares/dst052
70. Norden, D. M., and Godbout, J. P. (2013). Review: microglia of the aged brain: primed to be activated and resistant to regulation. Neuropathol. Appl. Neurobiol. 39, 19-34. doi: 10.1111/j.1365-2990.2012.01306.x
71. Olsen, I., and Singhrao, S. K. (2015). Can oral infection be a risk factor for Alzheimer's disease? J. Oral Microbiol. 7:29143. doi: 10.3402/jom.v7.29143
72. Olsen, I., and Singhrao, S. K. (2016). Inflammasome involvement in Alzheimer's disease. J. Alzheimers Dis. 54, 45-53. doi: 10.3233/JAD-160197
73. Pace, N. R. (1997). A molecular view of microbial diversity and the biosphere. Science 276, 734-740. doi: 10.1126/science.276.5313.734
74. Paganini-Hill, A., White, S. C., and Atchison, K. A. (2012). Dentition, dental health habits and dementia: the leisure world cohort study. J. Am. Geriatr. Soc. 60, 1556-1563. doi: 10.1111/j.1532-5415.2012.04064.x
75. Paisse, S., Valle, C., Servant, F., Courtney, M., Burcelin, R., Amar, J., et al. (2016). Comprehensive description of blood microbiome from healthy donors assessed by 16s targeted metagenomic sequencing. Transfusion 56, 1138-1147. doi: 10.1111/trf.13477
76. Perlmutter, L. S., and Chui, H. C. (1990). Microangiopathy, the vascular basement membrane and Alzheimer's disease: a review. Brain Res. Bull. 24, 677-686. doi: 10.1016/0361-9230(90)90007-m
77. Perry, V. H., and Holmes, C. (2014). Microglial priming in neurodegenerative disease. Nat. Rev. Neurol. 10, 217-224. doi: 10.1038/nrneurol.2014.38
78. Perry, V. H., Nicoll, J. A., and Holmes, C. (2010). Microglia in neurodegenerative disease. Nat. Rev. Neurol. 6, 193-201. doi: 10.1038/nrneurol.2010.17
79. Pisa, D., Alonso, R., Rábano, A., Rodal, I., and Carrasco, L. (2015). Different brain regions are infected with fungi in Alzheimer's disease. Sci. Rep. 5:15015. doi: 10.1038/srep15015
80. Price, M. N., Dehal, P. S., and Arkin, A. P. (2010). Fasttree 2-approximately maximum-likelihood trees for large alignments. PLoS One 5:e9490. doi: 10.1371/journal.pone.0009490
81. Price, J. L., and Morris, J. C. (1999). Tangles and plaques in nondemented aging and 'preclinical' Alzheimer's disease. Ann. Neurol. 45, 358-368. doi: 10.1002/1531-8249(199903)45:3<358::AID-ANA12>3.0.CO;2-X
82. Prolla, T. A. (2002). DNA microarray analysis of the aging brain. Chem. Senses 27, 299-306. doi: 10.1093/chemse/27.3.299
83. Qin, J., Li, Y., Cai, Z., Li, S., Zhu, J., Zhang, F., et al. (2012). A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55-60. doi: 10.1038/nature11450
84. Riviere, G. R., Riviere, K. H., and Smith, K. S. (2002). Molecular and immunological evidence of oral treponema in the human brain and their association with Alzheimer's disease. Oral Microbiol. Immunol. 17, 113-118. doi: 10.1046/j.0902-0055.2001.00100.x
85. Rylev, M., and Kilian, M. (2008). Prevalence and distribution of principal periodontal pathogens worldwide. J. Clin. Periodontol. 35, 346-361. doi: 10.1111/j.1600-051x.2008.01280.x
86. Salter, S. J., Cox, M. J., Turek, E. M., Calus, S. T., Cookson, W. O., Moffatt, M. F., et al. (2014). Reagent and laboratory contamination can critically impact sequence-based microbiome analyses. BMC Biol. 12:87. doi: 10.1186/s12915-014-0087-z
87. Salzberg, S. L., Breitwieser, F. P., Kumar, A., Hao, H., Burger, P., Rodriguez, F. J., et al. (2016). Next-generation sequencing in neuropathologic diagnosis of infections of the nervous system. Neurol. Neuroimmunol. Neuroinflamm. 3:e251. doi: 10.1212/NXI.0000000000000251
88. Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri, G. G., Ilhan, Z. E., et al. (2016). Gut microbiota regulate motor deficits and neuroinflammation in a model of parkinson's disease. Cell 167, 1469-1480.e12. doi: 10.1016/j.cell.2016.11.018
89. Sanz, M., van Winkelhoff, A. J., Herrera, D., Dellemijn-Kippuw, N., Simón, R., and Winkel, E. (2000). Differences in the composition of the subgingival microbiota of two periodontitis populations of different geographical origin. A comparison between spain and the netherlands. Eur. J. Oral Sci. 108, 383-392. doi: 10.1034/j.1600-0722.2000.108005383.x
90. Sastre, M., Klockgether, T., and Heneka, M. T. (2006). Contribution of inflammatory processes to Alzheimer's disease: molecular mechanisms. Int. J. Dev. Neurosci. 24, 167-176. doi: 10.1016/j.ijdevneu.2005.11.014
91. Shoemark, D. K., and Allen, S. J. (2015). The microbiome and disease: reviewing the links between the oral microbiome, aging, and Alzheimer's disease. J. Alzheimers Dis. 43, 725-738. doi: 10.3233/JAD-141170
92. Soscia, S. J., Kirby, J. E., Washicosky, K. J., Tucker, S. M., Ingelsson, M., Hyman, B., et al. (2010). The Alzheimer's disease-associated amyloid β-protein is an antimicrobial peptide. PLoS One 5:e9505. doi: 10.1371/journal.pone.0009505
93. Sparks Stein, P., Steffen, M. J., Smith, C., Jicha, G., Ebersole, J. L., Abner, E., et al. (2012). Serum antibodies to periodontal pathogens are a risk factor for Alzheimer's disease. Alzheimers Dement. 8, 196-203. doi: 10.1016/j.jalz.2011.04.006
94. Spitzer, P., Condic, M., Herrmann, M., Oberstein, T. J., Scharin-Mehlmann, M., Gilbert, D. F., et al. (2016). Amyloidogenic amyloid-β-peptide variants induce microbial agglutination and exert antimicrobial activity. Sci. Rep. 6:32228. doi: 10.1038/srep32228
95. Stein, P. S., Desrosiers, M., Donegan, S. J., Yepes, J. F., and Kryscio, R. J. (2007). Tooth loss, dementia and neuropathology in the nun study. J. Am. Dent. Assoc. 138, 1314-1322; quiz 1381-1312. doi: 10.1038/bdj.2007.1025
96. Stewart, E. J. (2012). Growing unculturable bacteria. J. Bacteriol. 194, 4151-4160. doi: 10.1128/jb.00345-12
97. Sudduth, T. L., Schmitt, F. A., Nelson, P. T., and Wilcock, D. M. (2013). Neuroinflammatory phenotype in early Alzheimer's disease. Neurobiol. Aging 34, 1051-1059. doi: 10.1016/j.neurobiolaging.2012.09.012
98. Tanghetti, E. A. (2013). The role of inflammation in the pathology of acne. J. Clin. Aesthet. Dermatol. 6, 27-35
99. Tarkowski, E., Blennow, K., Wallin, A., and Tarkowski, A. (1999). Intracerebral production of tumor necrosis factor-a, a local neuroprotective agent, in Alzheimer disease and vascular dementia. J. Clin. Immunol. 19, 223-230. doi: 10.1023/A:1020568013953
100. Tosto, G., and Reitz, C. (2013). Genome-wide association studies in Alzheimer's disease: a review. Curr. Neurol. Neurosci. Rep. 13:381. doi: 10.1007/s11910-013-0381-0
101. Tran, L., and Greenwood-Van Meerveld, B. (2013). Age-associated remodeling of the intestinal epithelial barrier. J. Gerontol. A Biol. Sci. Med. Sci. 68, 1045-1056. doi: 10.1093/gerona/glt106
102. Tringe, S. G., and Hugenholtz, P. (2008). A renaissance for the pioneering 16s rrna gene. Curr. Opin. Microbiol. 11, 442-446. doi: 10.1016/j.mib.2008.09.011
103. Turnbaugh, P. J., Hamady, M., Yatsunenko, T., Cantarel, B. L., Duncan, A., Ley, R. E., et al. (2009). A core gut microbiome in obese and lean twins. Nature 457, 480-484. doi: 10.1038/nature07540
104. Vázquez-Baeza, Y., Pirrung, M., Gonzalez, A., and Knight, R. (2013). EMPeror: a tool for visualizing high-throughput microbial community data. Gigascience 2:16. doi: 10.1186/2047-217x-2-16
105. Weksler, M. E., Gouras, G., Relkin, N. R., and Szabo, P. (2005). The immune system, amyloid-β peptide and Alzheimer's disease. Immunol. Rev. 205, 244-256. doi: 10.1111/j.0105-2896.2005.00264.x
106. Woese, C. R. (1987). Bacterial evolution. Microbiol. Rev. 51, 221-271
107. Woese, C. R., and Fox, G. E. (1977). Phylogenetic structure of the prokaryotic domain: the primary kingdoms. Proc. Natl. Acad. Sci. U S A 74, 5088-5090. doi: 10.1073/pnas.74.11.5088
108. Woese, C. R., Stackebrandt, E., Macke, T. J., and Fox, G. E. (1985). A phylogenetic definition of the major eubacterial taxa. Syst. Appl. Microbiol. 6, 143-151. doi: 10.1016/s0723-2020(85)80047-3
109. Yu, J.-T., Tan, L., and Hardy, J. (2014). Apolipoprotein e in Alzheimer's disease: an update. Annu. Rev. Neurosci. 37, 79-100. doi: 10.1146/annurev-neuro-071013-014300
110. Zhan, X., Stamova, B., Jin, L.-W., Decarli, C., Phinney, B., and Sharp, F. R. (2016). Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology 87, 2324-2332. doi: 10.1212/wnl.0000000000003391