본문 바로가기
KERD
논문KCI 등재

Current understanding of the Alzheimer’s disease-associated microbiome and therapeutic strategies

Seo Dong-oh|Holtzman David M.
생화학분자생물학회 (Korean Society Of Biochemistry And Molecular Biology)|2024.12|Experimental and Molecular Medicine|제56권 |pp. 86-94|DOI 10.1038/s12276-023-01146-2

2

조회

0

다운로드

1

인용

0

참고문헌

주제분류생화학

초록

Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disease. Despite tremendous research efforts to understand this complex disease, the exact pathophysiology of the disease is not completely clear. Recently, anti-Aβ antibodies have been shown to remove amyloid from the brain and slow the clinical progression of mild dementia by ~30%. However, exploring alternative strategies is crucial to understanding and developing more effective therapeutic interventions. In recent years, the microbiota-gut-brain axis has received significant attention in the AD field. Numerous studies have suggested that alterations in the gut microbiota composition are associated with the progression of AD, and several underlying mechanisms have been proposed. However, studies in this area are still in their infancy, and many aspects of this field are just beginning to be explored and understood. Gaining a deeper understanding of the intricate interactions and signaling pathways involved in the microbiota-AD interaction is crucial for optimizing therapeutic strategies targeting gut microbiota to positively impact AD. In this review, we aim to summarize the current understanding of the microbiota-gut-brain axis in AD. We will discuss the existing evidence regarding the role of gut microbiota in AD pathogenesis, suggested underlying mechanisms, biological factors influencing the microbiome-gut-brain axis in AD, and remaining questions in the field. Last, we will discuss potential therapeutic approaches to recondition the community of gut microbiota to alleviate disease progression. An ongoing exploration of the gut-brain axis and the development of microbiota-based therapies hold the potential for advancing AD management in the future.

Abstract

Alzheimer’s disease (AD) is a fatal progressive neurodegenerative disease. Despite tremendous research efforts to understand this complex disease, the exact pathophysiology of the disease is not completely clear. Recently, anti-Aβ antibodies have been shown to remove amyloid from the brain and slow the clinical progression of mild dementia by ~30%. However, exploring alternative strategies is crucial to understanding and developing more effective therapeutic interventions. In recent years, the microbiota-gut-brain axis has received significant attention in the AD field. Numerous studies have suggested that alterations in the gut microbiota composition are associated with the progression of AD, and several underlying mechanisms have been proposed. However, studies in this area are still in their infancy, and many aspects of this field are just beginning to be explored and understood. Gaining a deeper understanding of the intricate interactions and signaling pathways involved in the microbiota-AD interaction is crucial for optimizing therapeutic strategies targeting gut microbiota to positively impact AD. In this review, we aim to summarize the current understanding of the microbiota-gut-brain axis in AD. We will discuss the existing evidence regarding the role of gut microbiota in AD pathogenesis, suggested underlying mechanisms, biological factors influencing the microbiome-gut-brain axis in AD, and remaining questions in the field. Last, we will discuss potential therapeutic approaches to recondition the community of gut microbiota to alleviate disease progression. An ongoing exploration of the gut-brain axis and the development of microbiota-based therapies hold the potential for advancing AD management in the future.

참고문헌 (97)

  1. Long, J., "Alzheimer disease : an update on pathobiology and treatment strategies", Cell, 179, pp.312~339 (2019)
  2. Agirman, G., "Signaling inflammation across the gut-brain axis", Science, 374, pp.1087~1092 (2021)
  3. Seo, D. O., "Gut microbiota : from the forgotten organ to a potential key player in the pathology of Alzheimer’s disease", J. Gerontol. A Biol. Sci. Med. Sci, 75, pp.1232~1241 (2020)
  4. Moore, A. M., "Contextualising the microbiota-gut-brain axis in history and culture", Micro. Ecol. Health Dis, 30, pp.1546267~ (2019)
  5. Bharti, R., "Current challenges and best-practice protocols for microbiome analysis", Brief. Bioinform, 22, pp.178~193 (2021)
  6. Cattaneo, A., "Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly", Neurobiol. Aging, 49, pp.60~68 (2017)
  7. Vogt, N. M., "Gut microbiome alterations in Alzheimer’s disease", Sci. Rep, 7, pp.13537~ (2017)
  8. Jemimah, S., "Gut microbiome dysbiosis in Alzheimer’s disease and mild cognitive impairment: A systematic review and meta-analysis", PLoS ONE, 18, pp.e0285346~ (2023)
  9. Ferreiro, A. L., "Gut microbiome composition may be an indicator of pre clinical Alzheimer’s disease", Sci. Transl. Med, 15, pp.eabo2984~ (2023)
  10. Zhuang, Z. Q., "Gut microbiota is altered in patients with Alzheimer’s disease", J. Alzheimers Dis, 63, pp.1337~1346 (2018)
  11. Brandscheid, C., "Altered gut microbiome composition and tryptic activity of the 5xFAD Alzheimer’s mouse model", J. Alzheimers Dis, 56, pp.775~788 (2017)
  12. Chen, C., "Gut microbiota regulate Alzheimer’s disease pathologies and cognitive disorders via PUFA-associated neuroinflammation", Gut, 71, pp.2233~2252 (2022)
  13. Sun, B. L., "Gut microbiota alteration and its time course in a tauopathy mouse model", J. Alzheimers Dis, 70, pp.399~412 (2019)
  14. Ursell, L. K., "The interpersonal and intrapersonal diversity of human associated microbiota in key body sites", J. Allergy Clin. Immunol, 129, pp.1204~1208 (2012)
  15. Human, M. P. C., "Structure, function and diversity of the healthy human micro biome", Nature, 486, pp.207~214 (2012)
  16. Turnbaugh, P. J., "A core gut microbiome in obese and lean twins", Nature, 457, pp.480~484 (2009)
  17. Lozupone, C. A., "Diversity, stability and resilience of the human gut microbiota", Nature, 489, pp.220~230 (2012)
  18. Fetzer, I., "The extent of functional redundancy changes as species’ roles shift in different environments", Proc. Natl Acad. Sci. USA, 112, pp.14888~14893 (2015)
  19. Harach, T., "Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota", Sci. Rep, 7, pp.41802~ (2017)
  20. Dodiya, H. B., "Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes", J. Exp. Med, 216, pp.1542~1560 (2019)
  21. Wang, X. L., "Helicobacter pylori filtrate impairs spatial learning and memory in rats and increases β-amyloid by enhancing expression of presenilin-2", Front. Aging Neurosci, 6, pp.66~ (2014)
  22. Kim, M. S., "Transfer of a healthy microbiota reduces amyloid and tau pathology in an Alzheimer’s disease animal model", Gut, 69, pp.283~294 (2020)
  23. Seo, D. O., "ApoE isoform- and microbiota-dependent progression of neu rodegeneration in a mouse model of tauopathy", Science, 379, pp.eadd1236~ (2023)
  24. Koyuncu, O. O., "Virus infections in the nervous system", Cell Host Microbe, 13, pp.379~393 (2013)
  25. Itzhaki, R. F., "Microbes and Alzheimer’s disease", J. Alzheimers Dis, 51, pp.979~984 (2016)
  26. Seaks, C. E., "Infectious hypothesis of Alzheimer disease", PLoS Pathog, 16, pp.e1008596~ (2020)
  27. Readhead, B., "Multiscale analysis of independent Alzheimer’s cohorts finds disruption of molecular, genetic, and clinical networks by human herpesvirus", Neuron, 99, pp.64~82 (2018)
  28. Tzeng, N. S., "Anti-herpetic medications and reduced risk of dementia in patients with herpes simplex virus infections—a nationwide, population-based cohort study in Taiwan", Neurotherapeutics, 15, pp.417~429 (2018)
  29. Senejani, A. G., "Borrelia burgdorferi Co-Localizing with Amyloid Markers in Alzheimer’s Disease Brain Tissues", J. Alzheimers Dis, 85, pp.889~903 (2022)
  30. Chacko, A., "Chlamydia pneumoniae can infect the central nervous system via the olfactory and trigeminal nerves and contributes to Alzheimer’s disease risk", Sci. Rep, 12, pp.2759~ (2022)
  31. Dominy, S. S., "Porphyromonas gingivalis in Alzheimer’s disease brains: Evi dence for disease causation and treatment with small-molecule inhibitors", Sci. Adv, 5, pp.eaau3333~ (2019)
  32. Moir, R. D., "The antimicrobial protection hypothesis of Alzheimer’s disease", Alzheimers Dement, 14, pp.1602~1614 (2018)
  33. Eimer, W. A., "Alzheimer’s disease-associated β-amyloid is rapidly seeded by herpesviridae to protect against brain infection", Neuron, 99, pp.56~63 (2018)
  34. Wu, Y., "Microglia and amyloid precursor protein coordinate control of transient Candida cerebritis with memory deficits", Nat. Commun, 10, pp.685~ (2019)
  35. "Translocation of gut commensal bacteria to the brain" (2023)[URL]
  36. Friedland, R. P., "The role of microbial amyloid in neurode generation", PLoS Pathog, 13, pp.e1006654~ (2017)
  37. Schäfer, K. H., "Intra-gastrointestinal amyloid-β1–42oligomers perturb enteric function and induce Alzheimer’s disease pathology", J. Physiol, 598, pp.4141~4142 (2020)
  38. Jin, J., "Gut-derived β-amyloid : Likely a centerpiece of the gut-brain axis contributing to Alzheimer’s pathogenesis", Gut Microbes, 15, pp.2167172~ (2023)
  39. Shi, Y., "Interplay between innate immunity and Alzheimer disease : APOE and TREM2 in the spotlight", Nat. Rev. Immunol, 18, pp.759~772 (2018)
  40. Brandebura, A. N., "Astrocyte contribution to dysfunction, risk and progression in neurodegenerative disorders", Nat. Rev. Neurosci, 24, pp.23~39 (2023)
  41. Erny, D., "Host microbiota constantly control maturation and function of microglia in the CNS", Nat. Neurosci, 18, pp.965~977 (2015)
  42. Thion, M. S., "Microbiome influences prenatal and adult microglia in a sex specific manner", Cell, 172, pp.500~516 (2018)
  43. Hanamsagar, R., "Generation of a microglial developmental index in mice and in humans reveals a sex difference in maturation and immune reactivity", Glia, 66, pp.460~ (2018)
  44. Matcovitch-Natan, O., "Microglia development follows a stepwise program to regulate brain homeostasis", Science, 353, pp.aad8670~ (2016)
  45. Spichak, S., "Microbially-derived short-chain fatty acids impact astrocyte gene expression in a sex-specific manner", Brain Behav. Immun. Health, 16, pp.100318~ (2021)
  46. Erny, D., "Microbiota-derived acetate enables the metabolic fitness of the brain innate immune system during health and disease", Cell Metab, 33, pp.2260~2276 (2021)
  47. Mezö, C., "Different effects of constitutive and induced microbiota modula tion on microglia in a mouse model of Alzheimer’s disease", Acta Neuropathol. Commun, 8, pp.119~ (2020)
  48. Dodiya, H. B., "Gut microbiota-driven brain Aβ amyloidosis in mice requires microglia", J. Exp. Med, 219, pp.e20200895~ (2022)
  49. Hou, K., "Microbiota in health and diseases", Signal. Transduct. Target Ther, 7, pp.135~ (2022)
  50. Marizzoni, M., "A peripheral signature of Alzheimer’s disease featuring microbiota-gut-brain axis markers", Alzheimers Res. Ther, 15, pp.101~ (2023)
  51. Bettcher, B. M., "Peripheral and central immune system crosstalk in Alzheimer disease—a research prospectus", Nat. Rev. Neurol, 17, pp.689~701 (2021)
  52. Minter, M. R., "Antibiotic-induced perturbations in gut microbial diversity influences neuro-inflammation and amyloidosis in a murine model of Alzheimer’s disease", Sci. Rep, 6, pp.30028~ (2016)
  53. Köhler, C. A., "Peripheral cytokine and chemokine alterations in depression : a meta-analysis of 82 studies", Acta Psychiatr. Scand, 135, pp.373~387 (2017)
  54. Bell, R. D., "Apolipoprotein E controls cerebrovascular integrity via cyclophilin A", Nature, 485, pp.512~516 (2012)
  55. Montagne, A., "APOE4 accelerates advanced-stage vascular and neurode generative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β", Nat. Aging, 1, pp.506~520 (2021)
  56. Tang, Y., "Short-chain fatty acids induced autophagy serves as an adaptive strategy for retarding mitochondria-mediated apoptotic cell death", Cell Death Differ, 18, pp.602~618 (2011)
  57. den Besten, G., "The role of short-chain fatty acids in the interplay between diet, gut microbiota, and host energy metabolism", J. Lipid Res, 54, pp.2325~2340 (2013)
  58. Boland, B., "Autophagy induction and autophagosome clearance in neurons : relationship to autophagic pathology in Alzheimer’s disease", J. Neurosci, 28, pp.6926~6937 (2008)
  59. Bonfili, L., "Microbiota modulation counteracts Alzheimer’s disease progres sion influencing neuronal proteolysis and gut hormones plasma levels", Sci. Rep, 7, pp.2426~ (2017)
  60. Choi, H., "Functional effects of gut microbiota-derived metabolites in Alzheimer’s disease", Curr. Opin. Neurobiol, 81, pp.102730~ (2023)
  61. Dalile, B., "The role of short-chain fatty acids in microbiota-gut-brain communication", Nat. Rev. Gastroenterol. Hepatol, 16, pp.461~478 (2019)
  62. Smith, P. M., "The microbial metabolites, short-chain fatty acids, regulate colonic Treg cell homeostasis", Science, 341, pp.569~573 (2013)
  63. Arpaia, N., "Metabolites produced by commensal bacteria promote peripheral regulatory T-cell generation", Nature, 504, pp.451~455 (2013)
  64. Alves de Lima, K., "Meningeal γδ T cells regulate anxiety-like behavior via IL 17a signaling in neurons", Nat. Immunol, 21, pp.1421~1429 (2020)
  65. van der Hee, B., "Microbial regulation of host physiology by short chain fatty acids", Trends Microbiol, 29, pp.700~712 (2021)
  66. Sadler, R., "Short-chain fatty acids improve poststroke recovery via immu nological mechanisms", J. Neurosci, 40, pp.1162~1173 (2020)
  67. McMurran, C. E., "The microbiota regulates murine inflammatory responses to toxin-induced CNS demyelination but has minimal impact on remyelination", Proc. Natl Acad. Sci. USA, 116, pp.25311~25321 (2019)
  68. Abdel-Haq, R., "A prebiotic diet modulates microglial states and motor def icits in α-synuclein overexpressing mice", Elife, 11, pp.e81453~ (2022)
  69. Fernando, W. M. A. D. B., "Sodium butyrate reduces brain amyloid-β levels and improves cognitive memory performance in an Alzheimer’s disease trans genic mouse model at an early disease stage", J. Alzheimers Dis, 74, pp.91~99 (2020)
  70. Jiang, Y., "Sodium butyrate ameliorates the impair ment of synaptic plasticity by inhibiting the neuroinflammation in 5XFAD mice", Chem. Biol. Interact, 341, pp.109452~ (2021)
  71. Cuervo-Zanatta, D., "Dietary fiber modulates the release of gut bacterial products preventing cognitive decline in an Alzheimer’s mouse model", Cell Mol. Neurobiol, 43, pp.1595~1618 (2023)
  72. Killingsworth, J., "Propionate and Alzheimer’s disease", Front. Aging Neurosci, 12, pp.580001~ (2020)
  73. Baloni, P., "Metabolic network analysis reveals altered bile acid synthesis and metabolism in Alzheimer’s disease", Cell Rep. Med, 1, pp.100138~ (2020)
  74. Connell, E., "Microbial-derived metabolites as a risk factor of age-related cognitive decline and dementia", Mol. Neurodegener, 17, pp.43~ (2022)
  75. Vogt, N. M., "The gut microbiota-derived metabolite trimethylamine N-oxide is elevated in Alzheimer’s disease", Alzheimers Res. Ther, 10, pp.124~ (2018)
  76. Maier, L., "Extensive impact of non-antibiotic drugs on human gut bacteria", Nature, 555, pp.623~628 (2018)
  77. Rothschild, D., "Environment dominates over host genetics in shaping human gut microbiota", Nature, 555, pp.210~215 (2018)
  78. Parikh, I. J., "Murine gut microbiome association with APOE alleles", Front. Immunol, 11, pp.200~ (2020)
  79. Maldonado Weng, J., "Synergistic effects of APOE and sex on the gut microbiome of young EFAD transgenic mice", Mol. Neurodegener, 14, pp.47~ (2019)
  80. Tran, T. T. T., "APOE genotype influences the gut microbiome structure and function in humans and mice : relevance for Alzheimer’s disease pathophysiology", FASEB J, 33, pp.8221~8231 (2019)
  81. Vitek, M. P., "APOE genotype-specific differences in the innate immune response", Neurobiol. Aging, 30, pp.1350~1360 (2009)
  82. Klein, S. L., "Sex differences in immune responses", Nat. Rev. Immunol, 16, pp.626~638 (2016)
  83. Colton, C. A., "Sex steroids, APOE genotype and the innate immune system", Neurobiol. Aging, 26, pp.363~372 (2005)
  84. Hosang, L., "The lung microbiome regulates brain autoimmunity", Nature, 603, pp.138~144 (2022)
  85. Seo, D. O., "The microbiome : a target for Alzheimer disease", Cell Res, 29, pp.779~780 (2019)
  86. Francino, M. P., "Antibiotics and the human gut microbiome : dysbioses and accumulation of resistances", Front. Microbiol, 6, pp.1543~ (2015)
  87. Rakuša, E., "Sporadic use of antibiotics in older adults and the risk of dementia: a nested case-control study based on German Health Claims Data", J. Alzheimers Dis, 93, pp.1329~1339 (2023)
  88. Hazan, S., "Rapid improvement in Alzheimer’s disease symptoms following fecal microbiota transplantation : a case report", J. Int. Med. Res, 48, pp.300060520925930~ (2020)
  89. Park, S. H., "Cognitive function improvement after fecal microbiota trans plantation in Alzheimer’s dementia patient : a case report", Curr. Med. Res. Opin, 37, pp.1739~1744 (2021)
  90. Park, S. H., "Fecal microbiota transplantation can improve cognition in patients with cognitive decline and Clostridioides difficile infection", Aging (Albany NY), 14, pp.6449~6466 (2022)
  91. Akhgarjand, C., "Effects of probiotic supplements on cognition, anxiety, and physical activity in subjects with mild and moderate Alzheimer’s disease : a randomized, double-blind, and placebo-controlled study", Front. Aging Neurosci, 14, pp.1032494~ (2022)
  92. He, X., "The preventive effects of probiotic Akkermansia muciniphila on D galactose", AlCl3 mediated Alzheimer’s disease-like rats, 2022, pp.170, 111959~
  93. Zhu, G., "Bifidobacterium breve HNXY26M4attenuates cognitive deficits and neuroinflammation by regulating the gut–brain axis in APP", PS1 mice, 2023, pp.71, 4646~4655
  94. Bicknell, B., "Neurodegenerative and neurodevelopmental diseases and the gut-brain axis : the potential of therapeutic targeting of the microbiome", Int. J. Mol. Sci, 24, pp.9577~ (2023)
  95. Lancaster, S. M., "Global, distinctive, and personal changes in molecular and microbial profiles by specific fibers in humans", Cell Host Microbe, 30, pp.848~862 (2022)
  96. Sonnenburg, J. L., "Diet-microbiota interactions as moderators of human metabolism", Nature, 535, pp.56~64 (2016)
  97. Wang, X., "Sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit Alzheimer’s disease progression", Cell Res, 29, pp.787~803 (2019)

관련 논문AI추천

Exploring the Gut-Brain Connection: The Role of Microbiota in Alzheimer’s Disease PathogenesisAzizian Reza, Hamidi Masoud, Jafari Erfaneh, Mohammadi Mohammad Reza, Rahi Azar, Razmfarsa Atousa, Shakeri Hosseinabad Sara대한치매학회 · Dementia and Neurocognitive Disorders(대한치매학회지)2026 · 제25권 제1호Using Synbiotics as a Therapy to Protect Mental Health in Alzheimer's Disease양승환, Kim Dong Gyun, Ngoc Anh Pham Thi, Zahoor Adil한국미생물·생명공학회 · Journal of Microbiology and Biotechnology2024 · 제34권 제9호The potential role of gut microbiota-derived metabolites as regulators of metabolic syndrome-associated mitochondrial and endolysosomal dysfunction in Alzheimer’s disease정영현, Chae Chang Woo, Han Ho Jae생화학분자생물학회 · Experimental and Molecular Medicine2024 · 제56권 장내미생물과 퇴행성 신경질환과의 관계심다희, 홍광석학교체육연구소 · Asian Journal of Physical Education and Sport Science2023 · 제11권 제5호Association between Mild Cognitive Impairment and Gut Microbiota in Elderly Korean Patients김재홍, 손홍석, Cho Kwang-Moon, Kim Eun-Ju, Kim Jae-Seong, Kwon Sun Jae, Lee Mee-Hyun, Park Seong-Eun, Seo Seung-Ho한국미생물·생명공학회 · Journal of Microbiology and Biotechnology2023 · 제33권 제10호Regulation of common neurological disorders by gut microbial metabolitesKim Chang H., Park Jeongho생화학분자생물학회 · Experimental and Molecular Medicine2021 · 제53권

이 간행물의 다른 논문 (218건)

Big data and deep learning for RNA biologyJeon Hyeonseong, Baek Daehyun, Hwang Hyeonseo, Yeo Nagyeongpp. 1-29RGS19 activates the MYH9/β-catenin/c-Myc positive feedback loop in hepatocellular carcinomaXu Yanan, Ke Shanjia, Lu Shounan, Bai Miaoyu, Yu Hongjun, Yin Bing, Wang Chaoqun, Feng Zhigang, Li Zihao, Huang Jingjing, Li Xinglong, Qian Baolin, Hua Yongliang, Fu Yao, Sun Bei, Wu Yaohua, Ma Yongpp. 1-14Molecular mechanisms of circular RNA translationKim Yoon Ki, Hwang Hyun Jungpp. 1-9The m6A writer RBM15 drives the growth of triple-negative breast cancer cells through the stimulation of serine and glycine metabolismKim Ho, Yun Hye Jin, 이종호, Lee Su Bin, Kim Seok-Ho, Park Yun-Yong, Park Su Hwan, Ju Jin-Sung, Woo Hyunmin, Győrffy Balázs, Kim Eun-jeong, Han Hee Dong, Eyun Seong-ilpp. 1-15Neuron type-specific optogenetic stimulation for differential stroke recovery in chronic capsular infarctKim Ra Gyung, Cho Jongwook, Park Ji-Young, Kim Young Ro, Lee Min-Cheol, Kim Hyoung-Ihlpp. 1-11
원문 보기