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장내미생물과 인지기능은 서로 연관되어 있는가?

Does the Gut Microbiota Regulate a Cognitive Function?

  • 최정현 (인제대학교 보건의료융합대학 물리치료학과) ;
  • 진윤호 (인제대학교 보건의료융합대학 물리치료학과) ;
  • 김주헌 (경상대학교 수의과대학 동물의학연구소) ;
  • 홍용근 (인제대학교 보건의료융합대학 물리치료학과)
  • Choi, Jeonghyun (Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University) ;
  • Jin, Yunho (Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University) ;
  • Kim, Joo-Heon (Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University) ;
  • Hong, Yonggeun (Department of Physical Therapy, College of Healthcare Medical Science & Engineering, Inje University)
  • 투고 : 2019.06.09
  • 심사 : 2019.06.24
  • 발행 : 2019.06.30

초록

인지기능 저하는 장 단기 기억 및 주의력 소실과 우울증, 불안증의 증가를 특징으로 한다. 또한, 인지기능 저하는 알츠하이머, 파킨슨병과 같은 다양한 퇴행성 뇌질환과 연관되어 있다. 경제적 부담, 안전 위협을 포함하는 인지기능 저하와 관련된 사회적 문제는 고령화가 진행됨에 따라 증가하고 있다. 이러한 문제를 해결하기 위해 전 세계적으로 많은 연구가 수행되고 있다. 일반적으로 인지기능 저하를 유발할 가능성이 있는 원인으로는 노화에 따른 대사 및 호르몬 불균형, 감염, 약물 오남용, 신경세포 손상 등이 알려져 있지만 다양한 요인이 관련되어 있으므로 원인 규명이 어려운 한계점 때문에 뚜렷한 치료전략 수립이 어려운 실정이다. 최근의 연구에 따르면 퇴행성 뇌질환 발생의 원인과 이에 대한 치료전략 수립에 있어서 장내미생물의 역할이 중요하게 제시되고 있다. 특히, 알츠하이머병과 파킨슨병에서 장내미생물 조성의 변화 및 이들에 의한 대사산물에 따른 분자생물학적, 신경행동학적 증상의 변화가 밝혀졌다. 알츠하이머병 동물모델에서 장내미생물의 변화는 NMDA 수용체와 글루탐산의 변화를 통해 기억능력 소실을 야기하였다. 반면, 알츠하이머병 동물모델에 프로바이오틱스를 투여하였을 때, 비정상적인 신경학적 행동이 유의적으로 감소하였다. 파킨슨병은 장내미생물 군집의 변화와 직접적인 연관성을 보였으며 이는 이차적 증상인 변비 발생에도 영향을 미치는 것으로 나타났다. 파킨슨병 동물모델에 투여한 프로바이오틱스는 단쇄지방산 중 하나인 뷰티르산 증가를 통한 신경세포 보호효과를 나타내었다. 또한, 알츠하이머병과 파킨슨병에서 뇌-혈관장벽의 기능이상이 밝혀졌으며, 뇌-혈관장벽 변화는 장내미생물 불균형에 의한 전신성 염증에 따른 미세소관의 파괴 및 투과성 증가와 연관된 것으로 나타났다. 더불어 장내미생물 대사과정에서 생성된 대사산물은 퇴행성 뇌질환의 발생과 치료에 영향을 미친다. 본 논문에서는 인지기능 저하의 진행을 지연시킴으로써 심화를 방지할 수 있는 효과적인 접근법을 제시하기 위하여 인지기능 저하와 장내미생물의 연관성을 심층적으로 고찰하여 치료적 대안으로 제시하고자 한다.

Cognitive decline is characterized by reduced long-/short-term memory and attention span, and increased depression and anxiety. Such decline is associated with various degenerative brain disorders, especially Alzheimer's disease (AD) and Parkinson's disease (PD). The increases in elderly populations suffering from cognitive decline create social problems and impose economic burdens, and also pose safety threats; all of these problems have been extensively researched over the past several decades. Possible causes of cognitive decline include metabolic and hormone imbalance, infection, medication abuse, and neuronal changes associated with aging. However, no treatment for cognitive decline is available. In neurodegenerative diseases, changes in the gut microbiota and gut metabolites can alter molecular expression and neurobehavioral symptoms. Changes in the gut microbiota affect memory loss in AD via the downregulation of NMDA receptor expression and increased glutamate levels. Furthermore, the use of probiotics resulted in neurological improvement in an AD model. PD and gut microbiota dysbiosis are linked directly. This interrelationship affected the development of constipation, a secondary symptom in PD. In a PD model, the administration of probiotics prevented neuron death by increasing butyrate levels. Dysfunction of the blood-brain barrier (BBB) has been identified in AD and PD. Increased BBB permeability is also associated with gut microbiota dysbiosis, which led to the destruction of microtubules via systemic inflammation. Notably, metabolites of the gut microbiota may trigger either the development or attenuation of neurodegenerative disease. Here, we discuss the correlation between cognitive decline and the gut microbiota.

키워드

SMGHBM_2019_v29n6_747_f0001.png 이미지

Fig. 1. Involvement of the gut–brain axis in cognitive decline.

Table 1. Gastrointestinal tract and nervous system symptoms in subjects exhibiting cognitive decline

SMGHBM_2019_v29n6_747_t0001.png 이미지

참고문헌

  1. Aagaard, K., Ma, J., Antony, K. M., Ganu, R., Petrosino, J. and Versalovic, J. 2014. The placenta harbors a unique microbiome. Sci. Transl. Med. 6, 237ra65. https://doi.org/10.1126/scitranslmed.3008599
  2. Akbari, E., Asemi, Z., Daneshvar, Kakhaki, R., Bahmani, F., Kouchaki, E., Tamtaji, O. R., Hamidi, G. A. and Salami, M. 2016. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer's disease: A randomized, double-blind and controlled trial. Front. Aging. Neurosci. 8, 256.
  3. Bagyinszky, E., Giau, V. V., Shim, K., Suk, K., An, S. S. A. and Kim, S. 2017. Role of inflammatory molecules in the Alzheimer's disease progression and diagnosis. J. Neurol. Sci. 376, 242-254. https://doi.org/10.1016/j.jns.2017.03.031
  4. Baj, A., Moro, E., Bistoletti, M., Orlandi, V., Crema, F. and Giaroni, C. 2019. Glutamatergic signaling along the microbiota-gut-brain axis. Int. J. Mol. Sci. 20, E1482. https://doi.org/10.3390/ijms20061482
  5. Braniste, V., Al-Asmakh, M., Kowal, C., Anuar, F., Abbaspour, A., Toth, M., Korecka, A., Bakocevic, N., Ng, L. G., Kundu, P., Gulyas, B., Halldin, C., Hultenby, K., Nilsson, H., Hebert, H., Volpe, B. T., Diamond, B. and Pettersson, S. 2014. The gut microbiota influences blood-brain barrier permeability in mice. Sci. Transl. Med. 6, 263ra158. https://doi.org/10.1126/scitranslmed.3009759
  6. Browne, H. P., Veville, B. A., Forster, S. C. and Lawley, T. D. 2017. Transmission of the gut microbiota: spreading of health. Nat. Rev. Microbiol. 15, 531-543. https://doi.org/10.1038/nrmicro.2017.50
  7. Cai, H. Y., Yang, J. T., Wang, Z. J., Zhang, J., Yang, W., Wu, M. N. and Qi, J. S. 2018. Lixisenatide reduces amyloid plaques, neurofibrillary tangles and neuroinflammation in an APP/PS1/tau mouse model of Alzheimer's disease. Biochem. Biophys. Res. Commun. 495, 1034-1040. https://doi.org/10.1016/j.bbrc.2017.11.114
  8. Carney, R. S. E. D. 2019. Estrogen-dominant ovarian cycle stages are associated with neural network dysfunction and cognitive and behavioral deficits in the hAPP-J20 mouse model of Alzheimer's disease. eNeuro 6, e0179.
  9. Chen, W. W., Zhang, X. and Huang, W. J. 2016. Role of neuroinflammation in neurodegenerative disease (Review). Mol. Med. Rep. 13, 3391-3396. https://doi.org/10.3892/mmr.2016.4948
  10. Chio, C. C., Chang, C. H., Wang, C. C., Cheong, C. U., Chao, C. M., Cheng, B. C., Yang, C. Z. and Chang, C. P. 2013. Etanercept attenuates traumatic brain injury in rats by reducing early microglial expression of tumor necrosis factor-${\alpha}$. BMC Neurosci. 14, 33. https://doi.org/10.1186/1471-2202-14-33
  11. Choi, J., Hur, T. Y. and Hong, Y. 2018. Influence of altered gut microbiota composition on aging and aging-related diseases. J. Lifestyle Med. 8, 1-7. https://doi.org/10.15280/jlm.2018.8.1.1
  12. Choi, J., Lee, S., Won, J., Jin, Y., Hong, Y., Hur, T. Y., Kim, J. H., Lee, S. R. and Hong, Y. 2018. Pathophysiological and neurobehavioral characteristics of a propionic acid-mediated autism-like rat model. PLoS One 13, e0192925. https://doi.org/10.1371/journal.pone.0192925
  13. Collado, M. C., Rautava, S., Aakko, J., Isolauri, E. and Salminen, S. 2016. Human gut colonization may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci. Rep. 6, 23129. https://doi.org/10.1038/srep23129
  14. Dissanayaka, N. N. W., Lawson, R. A., Yarnall, A. J., Duncan, G. W., Breen, D. P., Khoo, T. K., Barker, R. A., Burn, D. J. and ICICLE-PD study group. 2017. Anxiety is associated with cognitive impairment in newly-diagnosed Parkinson's disease. Parkinsonism Relat. Disord. 36, 63-68. https://doi.org/10.1016/j.parkreldis.2017.01.001
  15. Dodiya, H. B., Forsyth, C. B., Voigt, R. M., Engen, P. A., Patel, J., Shaikh, M., Green, S. J., Nagib, A., Roy, A., Kordower, J. H, Pahan, K., Shannon, K. M. and Keshavarzian, A. 2018. Chronic stress-induced gut dysfunction exacerbates Parkinson's disease phenotype and pathology in a rotenone-induced mouse model of Parkinson's disease. Neurobiol. Dis. S0969-0061, 30768-X.
  16. Erdo, F., Denes, L. and de Lange, E. 2017. Age-associated physiological and pathological changes at the blood-brain barrier: A review. J. Cereb. Blood Flow Metab. 37, 4-24. https://doi.org/10.1177/0271678X16679420
  17. Franceschi, F., Ojetti, V., Candelli, M., Covino, M., Cardone, S., Potenza, A., Simeoni, B., Gabrielli, M., Sabia, L., Gasbarrini, G., Lopetuso, L., Scaldaferri, F., Rossini, P. M. and Gasbarrini, A. 2019. Microbes and Alzheimer's disease: lessons from H. pylori and gut microbiota. Eur. Rev. Med. Pharmacol. Sci. 23, 426-430.
  18. Frohlich, E. E., Farzi, A., Mayerhofer, R., Reichmann, F., Jacan, A., Wagner, B., Zinser, E., Bordag, N., Magnes, C., Frohlich, E., Kashoferm, K., Gorkiewicz, G. and Holzer, P. 2016. Cognitive impairment by antibiotic-induced gut dysbiosis: Analysis of gut microbiota-brain communication. Brain Behav. Immun. 56, 140-155. https://doi.org/10.1016/j.bbi.2016.02.020
  19. Funkhouser, L. J. and Bordenstein, S. R. 2013. Mom knows best: the universality of maternal microbial transmission. PLoS Biol. 11, e1001631. https://doi.org/10.1371/journal.pbio.1001631
  20. Garcez, M. L., Jacobs, K. R. and Guillemin, G. J. 2019. Microbiota alterations in Alzheimer's disease: Involvement of the kynurenine pathway and inflammation. Neurotox. Res. [Epub ahead of print]
  21. Gefen, T., Kim, G., Bolbolan, K., Geoly, A., Ohm, D., Oboudiyat, C., Shahidehpour, R., Rademaker, A., Weintraub, S., Bigio, E. H., Mesulam, M. M., Rogalski, E. and Geula, C. 2019. Activated microglia in cortical white matter across cognitive aging trajectories. Front. Aging Neurosci. 11, 94. https://doi.org/10.3389/fnagi.2019.00094
  22. Ghosh, S., Wu, M. D., Shaftel, S. S., Kyrkanides, S., LaFerla, F. M., Olschowka, J. A. and O'Banion, M. K. 2013. Sustained interleukin-$1{\beta}$ overexpression exacerbates tau pathology despite reduced amyloid burden in an Alzheimer's mouse model. J. Neurosci. 33, 5053-5064. https://doi.org/10.1523/JNEUROSCI.4361-12.2013
  23. Gray, M. T. and Woulfe, J. M. 2015. Striatal blood-brain barrier permeability in Parkinson's disease. J. Cereb. Blood Flow Metab. 35, 747-750. https://doi.org/10.1038/jcbfm.2015.32
  24. Ho, J. T., Chan, G. C. and Li, J. C. 2015. Systemic effects of gut microbiota and its relationship with disease and modulation. BMC Immunol. 16, 21. https://doi.org/10.1186/s12865-015-0083-2
  25. Holmgvist, S., Chutna, O., Bousset, L., Aldrin-Kirk, P., Li, W., Bjorklund, T., Wang, Z. Y., Roybon, L., Melki, R. and Li, J. Y. 2014. Direct evidence of Parkinson pathology spread from the gastrointestinal tract to the brain in rats. Acta Neuropathol. 128, 805-820. https://doi.org/10.1007/s00401-014-1343-6
  26. Ho, P. W., Leung, C. T., Liu, H., Pang, S. Y., Lam, C. S., Xian, J., Li, L., Kung, M. H., Ramsden, D. B. and Ho, S. L. 2019. Age-dependent accumulation of oligomeric SNCA/${\alpha}$-synuclein from impaired degradation in mutant LRRK2 knockin mouse model of Parkinson disease: role for therapeutic activation of chaperone-mediated autophagy (CMA). Autophagy 14, 1-24. https://doi.org/10.1080/15548627.2017.1386821
  27. Hoyles, L., Snelling, T., Umlai, U. K., Nicholson, J. K., Carding, S. R., Glen, R. C. and McArthur, S. 2018. Microbiome-host systems interaction: protective effects of propionate upon the blood-brain barrier. Microbiome 6, 55. https://doi.org/10.1186/s40168-018-0439-y
  28. Ianiro, G., Tilg, H. and Gasbarrini, A. 2016. Antibiotics a s deep modulators of gut microbiota: between good and evil. Gut 65, 1906-1915. https://doi.org/10.1136/gutjnl-2016-312297
  29. Isaacson, S. H., Boroojerdi, B., Waln, O., McGraw, M., Kreitzman, D. L., Klos, K., Revilla, F. J., Heldman, D., Phillips, M., Terricabras, D., Markowitz, M., Woltering, F., Carson, S. and Truong, D. 2019. Effect of using a wearable device on clinical decision-making and motor symptoms in patients with Parkinson's disease starting transdermal rotigotine patch: A pilot study. Parkinsonism Relat. Disord. S1353-8020, 30025-2.
  30. Iyer, K. K., Au, T. R., Angwin, A. J., Copland, D. A. and Dissanayaka, N. N. W. 2019. Source activity during emotion processing and its relationship to cognitive impairment in Parkinson's disease. J. Affect. Disord. 253, 327-335. https://doi.org/10.1016/j.jad.2019.05.012
  31. Jagust, W. 2018. Imaging the evolution and pathophysiology of Alzheimer's disease. Nat. Rev. Neurosci. 19, 687-700. https://doi.org/10.1038/s41583-018-0067-3
  32. Jin, Y., Choi, J., Won, J. and Hong, Y. 2018. The relationship between autism spectrum disorder and melatonin during fetal development. Molecules 23, E198. https://doi.org/10.3390/molecules23010198
  33. Kakutani, S., Watanabe, H. and Murayama, N. 2019. Green tea intake and risks for dementia, Alzheimer's disease, mild cognitive impairment, and cognitive impairment: A systemic review. Nutrients 11, E1165. https://doi.org/10.3390/nu11051165
  34. Kashyap, G., Bapat, D., Das, D., Gowaikar, R., Amritkar, R. E., Rangarajan, G., Ravindranath, V. and Ambika, G. 2019. Synapse loss and progress of Alzheimer's disease -A network model. Sci. Rep. 9, 6555. https://doi.org/10.1038/s41598-019-43076-y
  35. Kumar, M., Babaei, P. and Nielsen, J. 2016. Human gut microbiota and healthy aging: Recent developments and future prospective. Nutr. Healthy Aging 4, 3-16. https://doi.org/10.3233/NHA-150002
  36. Li, X. J., Hong, X. Y., Wang, Y. L., Zhang, S. J., Zhang, J. F., Li, X. C., Liu, Y. C., Sun, D. S., Feng, Q., Ye, J. W., Gao, Y., Ke, D., Wang, Q., Li, H. L., Ye, K., Liu, G. P. and Wang, J. Z. 2019. Tau accumulation triggers STAT-1-dependent memory deficits by suppressing NMDA receptor expression. EMBO Rep. e47202.
  37. Minter, M. R., Taylor, J. M. and Crack, P. J. 2016. The contribution of neuroinflammation of amyloid toxicity in Alzheimer's disease. J. Neurochem. 136, 457-474. https://doi.org/10.1111/jnc.13411
  38. Mutic, A. D., Jordan, S., Edwards, S. M., Ferranti, E. P., Thul, T. A. and Yang, I. 2017. The postpartum maternal and newborn microbiomes. MCN Am. J. Matern. Child Nurs. 42, 326-331. https://doi.org/10.1097/NMC.0000000000000374
  39. Neufeld, K. M., Kang, N., Bienenstock, J. and Foster, J. A. 2011. Reduced anxiety-like behavior and central neurochemical change in germ-free mice. Neurogastroenterol. Motil. 23, 255-264. https://doi.org/10.1111/j.1365-2982.2010.01620.x
  40. Neuman, H., Forsythe, P., Uzan, A., Avni, O. and Koren, O. 2018. Antibiotics in early life: dysbiosis and the damage done. FEMS Microbiol. Rev. 42, 489-499.
  41. Perez-Pardo, P., Dodiya, H. B., Engen, P. A., Forsyth, C. B., Huschens, A. M., Shaikh, M., Voigt, R. M., Nagib, A., Green, S. J., Kordower, J. H., Shannon, K. M., Garssen, J., Kraneveld, A. D. and Keshavarzian, A. 2019. Role of TLR4 in the gut-brain axis in Parkinson's disease: a translational study from men to mice. Gut 68, 829-843. https://doi.org/10.1136/gutjnl-2018-316844
  42. Robbins, T. W. 2011. Cognition: the ultimate brain function. Neuropsychopharmacology 36, 1-2. https://doi.org/10.1038/npp.2010.171
  43. Romo-Araiza, A., Gutierrez-Salmean, G., Galvan, E. J., Hernandez-Frausto, M., Herrera-Lopez, G., Romo-Parra, H., Garcia-Contreras, V., Fernandez-Presas, A. M., Jasso-Chavez, R., Borlongan, C. V. and Ibarra, A. 2018. Probiotics and prebiotics as a therapeutic strategy to improve memory on a model of middle-aged rats. Front. Aging Neurosci. 10, 416. https://doi.org/10.3389/fnagi.2018.00416
  44. Saji, N., Niida, S., Murotani, K., Hisada, T., Tsuduki, T., Sugimoto, T., Kimura, A., Toba, K. and Sakurai, T. 2019. Analysis of the relationship between the gut microbiome and dementia: a cross-sectional study conducted in Japan. Sci. Rep. 9, 1008. https://doi.org/10.1038/s41598-018-38218-7
  45. Sampson, T. R., Debelius, J. W., Thron, T., Janssen, S., Shastri, G. G., Ilhan, Z. E., Challis, C., Schretter, C. E., Rocha, S., Gradinaru, V., Chesselet, M. F., Keshavarzian, A., Shannon, K. M., Krajmalnik-Brown, R., Wittung-Stafshede, P., Knight, R. and Mazmanian, S. K. 2016. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson's disease. Cell 167, 1469-1480. https://doi.org/10.1016/j.cell.2016.11.018
  46. Saraswati, S. and Sitaraman, R. 2015. Aging and the human gut microbiota-from correlation to causality. Front. Microbiol. 5, 764. https://doi.org/10.3389/fmicb.2014.00764
  47. Sender, R., Fuchs, S. and Milo, R. 2016. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 14, e1002533. https://doi.org/10.1371/journal.pbio.1002533
  48. Shi, Y., Lu, X., Zhang, L., Shu, H., Gu, L., Wang, Z., Gao, L., Zhu, J., Zhang, H., Zhou, D. and Zhang, Z. J. 2019. Potential value of plasma Amyloid-${\beta}$, total tau and neurofilament light for identification of early Alzheimer's disease. ACS Chem. Neurosci. [Epub ahead of print].
  49. Srivastav, S., Neupane, S., Bhurtel, S., Katila, N., Maharjan, S., Choi, H., Hong, J. T. and Choi, D. Y. 2019. Probiotics mixture increases butyrate, and subsequently rescues the nigral dopaminergic neurons from MPTP and rotenone-induced neurotoxicity. J. Nutr. Biochem. 69, 73-86. https://doi.org/10.1016/j.jnutbio.2019.03.021
  50. Sudo, N., Chida, Y., Aiba, Y., Sonoda, J., Oyama, N., Yu, X. N., Kubo, C. and Koga, Y. 2004. Postnatal microbial colonization programs the hypothalamic-pituitary-adrenal system for stress response in mice. J. Physiol. 558, 263-275. https://doi.org/10.1113/jphysiol.2004.063388
  51. Tian, P., Wang, G., Zhao, J., Zhang, H. and Chen, W. 2019. Bifidobacterium with the role of 5-hydroxytryptophan synthesis regulation alleviates the symptom of depression and related microbiota dysbiosis. J. Nutr. Biochem. 66, 43-51. https://doi.org/10.1016/j.jnutbio.2019.01.007
  52. Vina, J. and Sanz-Ros, J. 2018. Alzheimer's disease: Only prevention makes sense. Eur. J. Clin. Invest. 48, e13005. https://doi.org/10.1111/eci.13005
  53. Wang, M. M., Miao, D., Cao, X. P., Tan, L. and Tan, L. 2018. Innate immune activation in Alzheimer's disease. Ann. Transl. Med. 6, 177. https://doi.org/10.21037/atm.2018.04.20
  54. Wang, T., Hu, X., Liang, S., Li, W., Wu, X., Wang, L. and Jin, F. 2015. Lactobacillus fermentum NS9 restores the antibiotic induced physiological and psychological abnormalities in rat. Benef. Microbes 6, 707-717. https://doi.org/10.3920/BM2014.0177
  55. Weil, R. S., Winston, J. S., Leyland, L. A., Pappa, K., Mahmood, R. B., Morris, H. R. and Rees, G. 2019. Neural correlates of early cognitive dysfunction in Parkinson's disease. Ann. Clin. Transl. Neurol. 6, 902-912. https://doi.org/10.1002/acn3.767
  56. Welcome, M. O. 2019. Gut microbiota disorder, gut epithelial and blood-brain barrier dysfunctions in etiopathogenesis of dementia: Molecular mechanisms and signaling pathways. Neuromolecular Med. [Epub ahead of print].
  57. Woodmansey, E. J. 2007. Intestinal bacteria and ageing. J. Appl. Microbiol. 102, 1178-1186. https://doi.org/10.1111/j.1365-2672.2007.03400.x