Advertisement

Current Geriatrics Reports

, Volume 7, Issue 2, pp 81–91 | Cite as

The Microbiome in Neurodegenerative Disease

  • Ethan G. Brown
  • Caroline M. Tanner
  • Samuel M. Goldman
Neurology of Aging (K Marder, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Neurology of Aging

Abstract

Purpose of Review

To review recent updates in our understanding of the microbiome and its relationship to neurodegenerative disease.

Recent Findings

Recognition of the microbiome’s role in health and disease continues to expand. Recent techniques have focused on delineating the function and metabolism of resident organisms, which may correlate more directly with human physiology than identification of species. The role of the microbiome may be of particular importance in certain neurodegenerative diseases, including Parkinson’s disease and Alzheimer’s disease, among others.

Summary

The microbiome influences brain function and may play a role in neurodegenerative disease. Potential mechanisms include immunologic activation and promotion/attenuation of inflammation, as well as direct effects on induction and/or exacerbation of protein aggregation. The microbiome also has increasingly well-documented effects on the metabolism of therapeutic medications. Future studies will need to work through complex methodologic issues in order to identify which changes are truly disease-specific. Nevertheless, manipulation of the microbiome may soon improve our ability to treat neurodegenerative disease.

Keywords

Microbiome Microbiota Neurodegeneration Parkinson’s disease Alzheimer’s disease Gut-brain axis 

Notes

Compliance with Ethical Standards

Conflict of Interest

Caroline Tanner reports personal fees from Adamas, Neurocrine, Photopharmics, Alexza, and 23andMe and fees from Voyager, Intec, and Biotie for DMC service. Samuel Goldman declares no conflict of interest. Ethan Brown reports personal fees from Abbvie, Inc., for serving on the Fellowship Advisory Board, outside the submitted work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    • Young VB. The role of the microbiome in human health and disease: an introduction for clinicians. BMJ. 2017;356:j831. This paper is a useful review of basics of microbiome research, aimed specifically at clinicians. PubMedCrossRefGoogle Scholar
  2. 2.
    Reyes A, Semenkovich NP, Whiteson K, Rohwer F, Gordon JI. Going viral: next-generation sequencing applied to phage populations in the human gut. Nat Rev Microbiol. 2012;10(9):607–17.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Huseyin CE, Rubio RC, O’Sullivan O, Cotter PD, Scanlan PD. The fungal frontier: a comparative analysis of methods used in the study of the human gut mycobiome. Front Microbiol. 2017;8:1432.PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Marzano V, Mancinelli L, Bracaglia G, del Chierico F, Vernocchi P, di Girolamo F, et al. “Omic” investigations of protozoa and worms for a deeper understanding of the human gut “parasitome”. PLoS Negl Trop Dis. 2017;11(11):e0005916.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Ursell LK, Clemente JC, Rideout JR, Gevers D, Caporaso JG, Knight R. The interpersonal and intrapersonal diversity of human-associated microbiota in key body sites. J Allergy Clin Immunol. 2012;129(5):1204–8.PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Foster KR, Schluter J, Coyte KZ, Rakoff-Nahoum S. The evolution of the host microbiome as an ecosystem on a leash. Nature. 2017;548(7665):43–51.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Lee YK, Mazmanian SK. Has the microbiota played a critical role in the evolution of the adaptive immune system? Science. 2010;330(6012):1768–73.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Morgan, X.C. and C. Huttenhower, Meta’omic analytic techniques for studying the intestinal microbiome. Gastroenterology, 2014;146(6): p. 1437–1448 e1.Google Scholar
  10. 10.
    Fraher MH, O'Toole PW, Quigley EM. Techniques used to characterize the gut microbiota: a guide for the clinician. Nat Rev Gastroenterol Hepatol. 2012;9(6):312–22.PubMedCrossRefGoogle Scholar
  11. 11.
    Shaffer M, Armstrong AJS, Phelan VV, Reisdorph N, Lozupone CA. Microbiome and metabolome data integration provides insight into health and disease. Transl Res. 2017;189:51–64.PubMedCrossRefGoogle Scholar
  12. 12.
    Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, et al. A core gut microbiome in obese and lean twins. Nature. 2009;457(7228):480–4.PubMedCrossRefGoogle Scholar
  13. 13.
    Tedjo DI, Jonkers DMAE, Savelkoul PH, Masclee AA, van Best N, Pierik MJ, et al. The effect of sampling and storage on the fecal microbiota composition in healthy and diseased subjects. PLoS One. 2015;10(5):e0126685.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Kuczynski J, Lauber CL, Walters WA, Parfrey LW, Clemente JC, Gevers D, et al. Experimental and analytical tools for studying the human microbiome. Nat Rev Genet. 2011;13(1):47–58.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    •• Brooks JP. Challenges for case-control studies with microbiome data. Ann Epidemiol. 2016;26(5):336–341 e1. This paper, along with others in the same series, highlights important statistical considerations when conducting and interpreting microbiome research. PubMedCrossRefGoogle Scholar
  16. 16.
    Gloor GB, Wu JR, Pawlowsky-Glahn V, Egozcue JJ. It’s all relative: analyzing microbiome data as compositions. Ann Epidemiol. 2016;26(5):322–9.PubMedCrossRefGoogle Scholar
  17. 17.
    Robinson CK, Brotman RM, Ravel J. Intricacies of assessing the human microbiome in epidemiologic studies. Ann Epidemiol. 2016;26(5):311–21.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Kaczmarek JL, Musaad SM, Holscher HD. Time of day and eating behaviors are associated with the composition and function of the human gastrointestinal microbiota. Am J Clin Nutr. 2017;106:1220–31.PubMedGoogle Scholar
  19. 19.
    Mai V, Prosperi M, Yaghjyan L. Moving microbiota research toward establishing causal associations that represent viable targets for effective public health interventions. Ann Epidemiol. 2016;26(5):306–10.PubMedCrossRefGoogle Scholar
  20. 20.
    Dominguez-Bello MG, Costello EK, Contreras M, Magris M, Hidalgo G, Fierer N, et al. Delivery mode shapes the acquisition and structure of the initial microbiota across multiple body habitats in newborns. Proc Natl Acad Sci U S A. 2010;107(26):11971–5.PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Rutayisire E, Huang K, Liu Y, Tao F. The mode of delivery affects the diversity and colonization pattern of the gut microbiota during the first year of infants’ life: a systematic review. BMC Gastroenterol. 2016;16(1):86.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Chu DM, Ma J, Prince AL, Antony KM, Seferovic MD, Aagaard KM. Maturation of the infant microbiome community structure and function across multiple body sites and in relation to mode of delivery. Nat Med. 2017;23(3):314–26.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Yatsunenko T, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486(7402):222–7.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Mariat D, Firmesse O, Levenez F, Guimarăes VD, Sokol H, Doré J, et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiol. 2009;9:123.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    • Woodmansey EJ. Intestinal bacteria and ageing. J Appl Microbiol. 2007;102(5):1178–86. A useful review of findings related to the gastrointestinal microbiome and aging. PubMedCrossRefGoogle Scholar
  26. 26.
    Odamaki T, Kato K, Sugahara H, Hashikura N, Takahashi S, Xiao JZ, et al. Age-related changes in gut microbiota composition from newborn to centenarian: a cross-sectional study. BMC Microbiol. 2016;16:90.PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    • Maffei VJ, et al. Biological aging and the human gut microbiota. J Gerontol A Biol Sci Med Sci. 2017;72(11):1474–82. This paper highlights an important perspective that understanding changes in the microbiome with age may require taking functional status and comorbid conditions into account. PubMedCrossRefGoogle Scholar
  28. 28.
    Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One. 2010;5(5):e10667.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    O’Toole PW, Jeffrey IB. Gut microbiota and aging. Science. 2015;350(6265):1214–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Kundu P, Blacher E, Elinav E, Pettersson S. Our gut microbiome: the evolving inner self. Cell. 2017;171(7):1481–93.PubMedCrossRefGoogle Scholar
  31. 31.
    Bailey MT, Dowd SE, Galley JD, Hufnagle AR, Allen RG, Lyte M. Exposure to a social stressor alters the structure of the intestinal microbiota: implications for stressor-induced immunomodulation. Brain Behav Immun. 2011;25(3):397–407.PubMedCrossRefGoogle Scholar
  32. 32.
    • Scheperjans, F., et al., Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord, 2015;30(3): p. 350-358. Early study examining differences between the microbiome in Parkinson’s disease compared with healthy controls. Google Scholar
  33. 33.
    Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, et al. Colonic bacterial composition in Parkinson's disease. Mov Disord. 2015;30(10):1351–60.PubMedCrossRefGoogle Scholar
  34. 34.
    Hasegawa S, Goto S, Tsuji H, Okuno T, Asahara T, Nomoto K, et al. Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson’s disease. PLoS One. 2015;10(11):e0142164.PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Bürmann J, et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord. 2016;32:66–72.PubMedCrossRefGoogle Scholar
  36. 36.
    Hill-Burns EM, Debelius JW, Morton JT, Wissemann WT, Lewis MR, Wallen ZD, et al. Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov Disord. 2017;32(5):739–49.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Petrov VA, Saltykova IV, Zhukova IA, Alifirova VM, Zhukova NG, Dorofeeva YB, et al. Analysis of gut microbiota in patients with Parkinson’s disease. Bull Exp Biol Med. 2017;162(6):734–7.PubMedCrossRefGoogle Scholar
  38. 38.
    Hopfner, F., et al., Gut microbiota in Parkinson disease in a northern German cohort. 2017.Google Scholar
  39. 39.
    Bedarf JR, Hildebrand F, Coelho LP, Sunagawa S, Bahram M, Goeser F, et al. Functional implications of microbial and viral gut metagenome changes in early stage L-DOPA-naive Parkinson's disease patients. Genome Med. 2017;9(1):39.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Noble JM, Scarmeas N, Celenti RS, Elkind MSV, Wright CB, Schupf N, et al. Serum IgG antibody levels to periodontal microbiota are associated with incident Alzheimer disease. PLoS One. 2014;9(12):e114959.PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    • Sparks Stein P, et al. Serum antibodies to periodontal pathogens are a risk factor for Alzheimer’s disease. Alzheimers Dement. 2012;8(3):196–203. Cross-sectional analysis suggesting that elevated serum antibodies to pathogenic bacteria of the oral microbiome are associated with Alzheimer’s disease. PubMedCrossRefGoogle Scholar
  42. 42.
    Poole S, Singhrao SK, Chukkapalli S, Rivera M, Velsko I, Kesavalu L, et al. Active invasion of Porphyromonas gingivalis and infection-induced complement activation in ApoE −/− mice brains. J Alzheimers Dis. 2015;43(1):67–80.PubMedGoogle Scholar
  43. 43.
    Emery DC, Shoemark DK, Batstone TE, Waterfall CM, Coghill JA, Cerajewska TL, et al. 16S rRNA next generation sequencing analysis shows bacteria in Alzheimer’s post-mortem brain. Front Aging Neurosci. 2017;9:195.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Cattaneo A, Cattane N, Galluzzi S, Provasi S, Lopizzo N, Festari C, 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.PubMedCrossRefGoogle Scholar
  45. 45.
    Poole S, Singhrao SK, Kesavalu L, Curtis MA, Crean S. Determining the presence of periodontopathic virulence factors in short-term postmortem Alzheimer’s disease brain tissue. J Alzheimers Dis. 2013;36(4):665–77.PubMedGoogle Scholar
  46. 46.
    •• Zhan X, et al. Gram-negative bacterial molecules associate with Alzheimer disease pathology. Neurology. 2016;87:2324–32. Autopsy study in which E . coli LPS are found at higher levels in the brains of patients with AD, and LPS is localized near amyloid protein aggregates. PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Rosas HD, Doros G, Bhasin S, Thomas B, Gevorkian S, Malarick K, et al. A systems-level “misunderstanding”: the plasma metabolome in Huntington’s disease. Ann Clin Transl Neurol. 2015;2(7):756–68.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Wu S, Yi J, Zhang YG, Zhou J, Sun J. Leaky intestine and impaired microbiome in an amyotrophic lateral sclerosis mouse model. Physiol Rep. 2015;3(4):e12356.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Zhang YG, Wu S, Yi J, Xia Y, Jin D, Zhou J, et al. Target intestinal microbiota to alleviate disease progression in amyotrophic lateral sclerosis. Clin Ther. 2017;39(2):322–36.PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Fang X, et al. Evaluation of the microbial diversity in amyotrophic lateral sclerosis using high-throughput sequencing. Front Microbiol. 2016;7:1479.PubMedPubMedCentralGoogle Scholar
  52. 52.
    Rowin J, Xia Y, Jung B, Sun J. Gut inflammation and dysbiosis in human motor neuron disease. Physiol Rep. 2017;5(18)Google Scholar
  53. 53.
    Brenner D, et al. The fecal microbiome of ALS patients. Neurobiol Aging. 2017;61:132–7.PubMedCrossRefGoogle Scholar
  54. 54.
    • Kelly, J.R., et al., Transferring the blues: Depression-associated gut microbiota induces neurobehavioural changes in the rat. J Psychiatr Res, 2016;82: p. 109-18. Study examining the differences in microbiota between patients with depression and healthy controls. Subsequent fecal transplantation from depressed patients led to behavioral changes in mice. Google Scholar
  55. 55.
    Cenit MC, Sanz Y, Codoner-Franch P. Influence of gut microbiota on neuropsychiatric disorders. World J Gastroenterol. 2017;23(30):5486–98.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Goodrich JK, Davenport ER, Beaumont M, Jackson MA, Knight R, Ober C, et al. Genetic determinants of the gut microbiome in UK twins. Cell Host Microbe. 2016;19(5):731–43.PubMedPubMedCentralCrossRefGoogle Scholar
  57. 57.
    Ley RE. The gene-microbe link. Nature. 2015;518:S7.PubMedCrossRefGoogle Scholar
  58. 58.
    Li E, Hamm CM, Gulati AS, Sartor RB, Chen H, Wu X, et al. Inflammatory bowel diseases phenotype, C. difficile and NOD2 genotype are associated with shifts in human ileum associated microbial composition. PLoS One. 2012;7(6):e26284.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Lamas B, Richard ML, Leducq V, Pham HP, Michel ML, da Costa G, et al. CARD9 impacts colitis by altering gut microbiota metabolism of tryptophan into aryl hydrocarbon receptor ligands. Nat Med. 2016;22(6):598–605.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Lim MY, You HJ, Yoon HS, Kwon B, Lee JY, Lee S, et al. The effect of heritability and host genetics on the gut microbiota and metabolic syndrome. Gut. 2017;66(6):1031–8.PubMedCrossRefGoogle Scholar
  61. 61.
    Turnbaugh PJ, et al. The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice. Sci Transl Med. 2009;1(6):6ra14.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    David LA, Maurice CF, Carmody RN, Gootenberg DB, Button JE, Wolfe BE, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505(7484):559–63.PubMedCrossRefGoogle Scholar
  63. 63.
    Singh RK, Chang HW, Yan D, Lee KM, Ucmak D, Wong K, et al. Influence of diet on the gut microbiome and implications for human health. J Transl Med. 2017;15(1):73.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Escobar JS, Klotz B, Valdes BE, Agudelo GM. The gut microbiota of Colombians differs from that of Americans, Europeans, and Asians. BMC Microbiol. 2014;14:311.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Biedermann L, Zeitz J, Mwinyi J, Sutter-Minder E, Rehman A, Ott SJ, et al. Smoking cessation induces profound changes in the composition of the intestinal microbiota in humans. PLoS One. 2013;8(3):e59260.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Ley RE, Turnbaugh PJ, Klein S, Gordon JI. Human gut microbes associated with obesity. Nature. 2006;444:1022–3.PubMedCrossRefGoogle Scholar
  67. 67.
    Allen JM, Mailing LJ, Niemiro GM, Moore R, Cook MD, White BA, et al. Exercise alters gut microbiota composition and function in lean and obese humans. Med Sci Sports Exerc. 2017;Google Scholar
  68. 68.
    •• Maurice CF, Haiser HJ, Turnbaugh PJ. Xenobiotics shape the physiology and gene expression of the active human gut microbiome. Cell. 2013;152(1–2):39–50. Comprehensive analysis of many types of medications and how they interact with the microbiome. PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Langdon A, Crook N, Dantas G. The effects of antibiotics on the microbiome throughout development and alternative approaches for therapeutic modulation. Genome Med. 2016;8(1):39.PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Jernberg C, Lofmark S, Edlund C, Jansson JK. Long-term impacts of antibiotic exposure on the human intestinal microbiota. Microbiology. 2010;156(Pt 11):3216–23.PubMedCrossRefGoogle Scholar
  71. 71.
    Patel R, DuPont HL. New approaches for bacteriotherapy: prebiotics, new-generation probiotics, and synbiotics. Clin Infect Dis. 2015;60(Suppl 2):S108–21.PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    • Cryan JF, Dinan TG. Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci. 2012;13(10):701–12. Thorough review on the microbiome’s effect on human behavior. PubMedCrossRefGoogle Scholar
  73. 73.
    •• Turnbaugh PJ, et al. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444(7122):1027–31. Key paper highlighting the relationship between obese and lean subjects and the transmissibility of adiposity to mice. PubMedCrossRefGoogle Scholar
  74. 74.
    van de Wouw M, Schellekens H, Dinan TG, Cryan JF. Microbiota-gut-brain axis: modulator of host metabolism and appetite. J Nutr. 2017;147(5):727–45.PubMedCrossRefGoogle Scholar
  75. 75.
    Vuong HE, Yano JM, Fung TC, Hsiao EY. The microbiome and host behavior. Annu Rev Neurosci. 2017;40:21–49.PubMedCrossRefGoogle Scholar
  76. 76.
    Cowan CSM, Hoban AE, Ventura-Silva AP, Dinan TG, Clarke G, Cryan JF. Gutsy moves: the amygdala as a critical node in microbiota to brain signaling. BioEssays. 2018;40(1)Google Scholar
  77. 77.
    Fetissov SO. Role of the gut microbiota in host appetite control: bacterial growth to animal feeding behaviour. Nat Rev Endocrinol. 2017;13(1):11–25.PubMedCrossRefGoogle Scholar
  78. 78.
    Luan H, Wang X, Cai Z. Mass spectrometry-based metabolomics: targeting the crosstalk between gut microbiota and brain in neurodegenerative disorders. Mass Spectrom Rev. 2017;Google Scholar
  79. 79.
    •• Fung TC, Olson CA, Hsiao EY. Interactions between the microbiota, immune and nervous systems in health and disease. Nat Neurosci. 2017;20(2):145–55. Useful and thorough review on mechanisms of how the microbiota affects the nervous system through the immune system. PubMedCrossRefGoogle Scholar
  80. 80.
    Bravo JA, Forsythe P, Chew MV, Escaravage E, Savignac HM, Dinan TG, 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 U S A. 2011;108(38):16050–5.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Spanogiannopoulos P, Bess EN, Carmody RN, Turnbaugh PJ. The microbial pharmacists within us: a metagenomic view of xenobiotic metabolism. Nat Rev Microbiol. 2016;14(5):273–87.PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Gu Y, Wang X, Li J, Zhang Y, Zhong H, Liu R, et al. Analyses of gut microbiota and plasma bile acids enable stratification of patients for antidiabetic treatment. Nat Commun. 2017;8(1):1785.PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Routy B, le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1–based immunotherapy against epithelial tumors. Science. 2018;359:91–7.PubMedCrossRefGoogle Scholar
  84. 84.
    Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti–PD-1 immunotherapy in melanoma patients. Science. 2018;359(6371):97–103.PubMedGoogle Scholar
  85. 85.
    Haiser HJ, Turnbaugh PJ. Is it time for a metagenomic basis of therapeutics? Science. 2012;336:1253–5.PubMedCrossRefGoogle Scholar
  86. 86.
    Poewe W. Non-motor symptoms in Parkinson’s disease. Eur J Neurol. 2008;15(Suppl 1):14–20.PubMedCrossRefGoogle Scholar
  87. 87.
    Braak H, de Vos RAI, Bohl J, del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett. 2006;396(1):67–72.PubMedCrossRefGoogle Scholar
  88. 88.
    Braak H, Rub U, Gai WP, del Tredici K. Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm. 2003;110(5):517–36.PubMedCrossRefGoogle Scholar
  89. 89.
    Holmqvist S, Chutna O, Bousset L, Aldrin-Kirk P, Li W, Björklund T, et al. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 2014;128(6):805–20.PubMedCrossRefGoogle Scholar
  90. 90.
    •• Sampson, Timothy R., et al., Gut microbiota regulate motor deficits and neuroinflammation in a model of parkinson’s disease. Cell, 2016;167(6): p. 1469-1480.e12. Seminal paper in supporting the causal effect of the microbiome on Parkinson’s disease using mouse models and fecal transplantation from patients. Google Scholar
  91. 91.
    Dobbs RJ, et al. Leukocyte-subset counts in idiopathic parkinsonism provide clues to a pathogenic pathway involving small intestinal bacterial overgrowth. A surveillance study. Gut Pathogens. 2012;4:12.PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Goldman SM, Kamel F, Ross GW, Jewell SA, Marras C, Hoppin JA, et al. Peptidoglycan recognition protein genes and risk of Parkinson’s disease. Mov Disord. 2014;29(9):1171–80.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Shen X, Yang H, Wu Y, Zhang D, Jiang H. Meta-analysis: Association of Helicobacter pylori infection with Parkinson’s diseases. Helicobacter. 2017;22(5)Google Scholar
  94. 94.
    Nielsen HH, Qiu J, Friis S, Wermuth L, Ritz B. Treatment for Helicobacter pylori infection and risk of Parkinson’s disease in Denmark. Eur J Neurol. 2012;19(6):864–9.PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Gorle N, et al. The choroid plexus epithelium as a novel player in the stomach-brain axis during Helicobacter infection. Brain Behav Immun. 2017;Google Scholar
  96. 96.
    Blaecher C, Smet A, Flahou B, Pasmans F, Ducatelle R, Taylor D, et al. Significantly higher frequency of Helicobacter suis in patients with idiopathic parkinsonism than in control patients. Aliment Pharmacol Ther. 2013;38(11–12):1347–53.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Hashim H, Azmin S, Razlan H, Yahya NW, Tan HJ, Manaf MRA, et al. Eradication of Helicobacter pylori infection improves levodopa action, clinical symptoms and quality of life in patients with Parkinson’s disease. PLoS One. 2014;9(11):e112330.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Gabrielli M, Bonazzi P, Scarpellini E, Bendia E, Lauritano EC, Fasano A, et al. Prevalence of small intestinal bacterial overgrowth in Parkinson's disease. Mov Disord. 2011;26(5):889–92.PubMedCrossRefGoogle Scholar
  99. 99.
    Heintz-Buschart A, et al. The nasal and gut microbiome in Parkinson’s disease and idiopathic rapid eye movement sleep behavior disorder. Mov Disord. 2017;Google Scholar
  100. 100.
    Pereira PAB, Aho VTE, Paulin L, Pekkonen E, Auvinen P, Scheperjans F. Oral and nasal microbiota in Parkinson’s disease. Parkinsonism RelatDisord. 2017;38:61–7.CrossRefGoogle Scholar
  101. 101.
    •• Forsyth, C.B., et al., Increased intestinal permeability correlates with sigmoid mucosa alpha-synuclein staining and endotoxin exposure markers in early Parkinson's disease. PLoS One, 2011;6(12): pe28032Small but intriguing study showing submucosal colonic E . coli invasion associated with alpha-synuclein aggregation. Google Scholar
  102. 102.
    Dutta G, Zhang P, Liu B. The lipopolysaccharide Parkinson’s disease animal model: mechanistic studies and drug discovery. Fundam Clin Pharmacol. 2008;22(5):453–64.PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Kelly LP, Carvey PM, Keshavarzian A, Shannon KM, Shaikh M, Bakay RAE, et al. Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease. Mov Disord. 2014;29(8):999–1009.PubMedCrossRefGoogle Scholar
  104. 104.
    Pal GD, et al. Abnormal lipopolysaccharide binding protein as marker of gastrointestinal inflammation in Parkinson disease. Front Neurosci. 2015;9:306.PubMedPubMedCentralCrossRefGoogle Scholar
  105. 105.
    Williams-Gray CH, Wijeyekoon R, Yarnall AJ, Lawson RA, Breen DP, Evans JR, et al. Serum immune markers and disease progression in an incident Parkinson’s disease cohort (ICICLE-PD). Mov Disord. 2016;31(7):995–1003.PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Hui, K.Y., et al., Functional variants in the LRRK2 gene confer shared effects on risk for Crohn’s disease and Parkinson’s disease. Sci Transl Med, 2018;10(423).Google Scholar
  107. 107.
    Goldin BR, Peppercorn MA, Goldman P. Contributions of host and intestinal microflora in the metabolism of L-DOPA by the rat. J Pharmacol Exp Ther. 1973;186(1):160–6.PubMedGoogle Scholar
  108. 108.
    Sandler M, et al. Therapeutic implications in parkinsonism of m-Tyramine formation from L-Dopa in man. Nature. 1971;229:414–6.PubMedCrossRefGoogle Scholar
  109. 109.
    Sanlder M, et al. Variation of levodopa metabolism with gastrointestinal absorption site. Lancet. 1974;303(7851):238–9.CrossRefGoogle Scholar
  110. 110.
    Fasano A, Bove F, Gabrielli M, Petracca M, Zocco MA, Ragazzoni E, et al. The role of small intestinal bacterial overgrowth in Parkinson’s disease. Mov Disord. 2013;28(9):1241–9.PubMedCrossRefGoogle Scholar
  111. 111.
    • Leira Y, et al. Is periodontal disease associated with Alzheimer’s disease? A systematic review with meta-analysis. Neuroepidemiology. 2017;48(1-2):21–31. Review of the clinical epidemiology data that identifies an association between periodontal disease and Alzheimer’s disease. PubMedCrossRefGoogle Scholar
  112. 112.
    Chen CK, Wu YT, Chang YC. Association between chronic periodontitis and the risk of Alzheimer's disease: a retrospective, population-based, matched-cohort study. Alzheimers Res Ther. 2017;9(1):56.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Ide M, Harris M, Stevens A, Sussams R, Hopkins V, Culliford D, et al. Periodontitis and cognitive decline in Alzheimer’s disease. PLoS One. 2016;11(3):e0151081.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Minter MR, Zhang C, Leone V, Ringus DL, Zhang X, Oyler-Castrillo P, et al. Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease. Sci Rep. 2016;6:30028.PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep. 2017;7(1):13537.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Pritchard AB, Crean SJ, Olsen I, Singhrao SK. Periodontitis, microbiomes and their role in Alzheimer’s disease. Front Aging Neurosci. 2017;9:336.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Wu Z, Ni J, Liu Y, Teeling JL, Takayama F, Collcutt A, et al. Cathepsin B plays a critical role in inducing Alzheimer's disease-like phenotypes following chronic systemic exposure to lipopolysaccharide from Porphyromonas gingivalis in mice. Brain Behav Immun. 2017;65:350–61.PubMedCrossRefGoogle Scholar
  118. 118.
    Mayeux R. Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003;26:81–104.PubMedCrossRefGoogle Scholar
  119. 119.
    Woolley JD, Khan BK, Murthy NK, Miller BL, Rankin KP. The diagnostic challenge of psychiatric symptoms in neurodegenerative disease: rates of and risk factors for prior psychiatric diagnosis in patients with early neurodegenerative disease. J Clin Psychiatry. 2011;72(2):126–33.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Ethan G. Brown
    • 1
  • Caroline M. Tanner
    • 2
  • Samuel M. Goldman
    • 3
  1. 1.Department of NeurologyUniversity of California-San FranciscoSan FranciscoUSA
  2. 2.Department of Neurology, San Francisco Veterans Affairs Health Care System, PADRECC (Parkinson’s Disease Research Education and Clinical Center)University of California-San FranciscoSan FranciscoUSA
  3. 3.Division of Occupational & Environmental Medicine & Department of Neurology, San Francisco Veterans Affairs Health Care SystemUniversity of California-San FranciscoSan FranciscoUSA

Personalised recommendations