Ghép vi khuẩn phân phục hồi bệnh Alzheimer trong chuột chuyển gen APP/PS1
Tóm tắt
Bệnh Alzheimer (AD) là loại sa sút trí tuệ phổ biến nhất ở người cao tuổi. Việc điều trị AD vẫn là một nhiệm vụ khó khăn trong lâm sàng. AD có liên quan đến hệ vi sinh vật đường ruột bất thường. Tuy nhiên, vẫn còn ít thông tin về vai trò của việc ghép vi khuẩn phân (FMT) trong AD. Ở đây, chúng tôi đã đánh giá hiệu quả của FMT trong việc điều trị AD. Chúng tôi đã sử dụng mô hình chuột chuyển gen APPswe/PS1dE9. Các khiếm khuyết về nhận thức, sự tích lũy amyloid-β (Aβ) trong não và sự phosphoryl hóa của tau, tính đàn hồi synapse cũng như viêm thần kinh đã được đánh giá. Hệ vi sinh vật đường ruột và các sản phẩm chuyển hóa của nó là các axit béo chuỗi ngắn (SCFAs) đã được phân tích bằng phương pháp giải trình tự 16S rRNA và 1H cộng hưởng từ hạt nhân (NMR). Kết quả của chúng tôi cho thấy rằng điều trị FMT có thể cải thiện các khiếm khuyết về nhận thức và giảm sự tích lũy amyloid-β (Aβ) trong chuột chuyển gen APPswe/PS1dE9. Những cải thiện này đi kèm với sự giảm phosphoryl hóa của protein tau và các mức độ của Aβ40 và Aβ42. Chúng tôi đã quan sát thấy sự gia tăng tính đàn hồi synapse trong chuột Tg, cho thấy rằng sự biểu hiện của protein mật độ hậu synapse 95 (PSD-95) và synapsin I đã tăng lên sau FMT. Chúng tôi cũng ghi nhận sự giảm của mức độ COX-2 và CD11b trong chuột Tg sau FMT. Chúng tôi cũng phát hiện ra rằng điều trị FMT đã đảo ngược sự thay đổi của hệ vi sinh vật đường ruột và SCFAs. Do đó, FMT có thể là một chiến lược điều trị tiềm năng cho AD.
Từ khóa
#Bệnh Alzheimer #chuyển gen #ghép vi khuẩn phân #vi sinh vật đường ruột #axit béo chuỗi ngắnTài liệu tham khảo
Jin, W. et al. Peritoneal dialysis reduces amyloid-beta plasma levels in humans and attenuates Alzheimer-associated phenotypes in an APP/PS1 mouse model. Acta Neuropathol. 134, 207–220 (2017).
Zhu, C., Xu, B., Sun, X., Zhu, Q. & Sui, Y. Targeting CCR3 to reduce amyloid-β production, Tau hyperphosphorylation, and synaptic loss in a mouse model of Alzheimer’s disease. Mol. Neurobiol. 54, 7964–7978 (2017).
Jiang, C., Li, G., Huang, P., Liu, Z. & Zhao, B. The gut microbiota and Alzheimer’s disease. J. Alzheimers Dis. 58, 1–15 (2017).
Zhuang, Z. Q. et al. Gut microbiota is altered in patients with Alzheimer’s disease. J. Alzheimers Dis. 63, 1337–1346 (2018).
Shen, L., Liu, L. & Ji, H. F. Alzheimer’s disease histological and behavioral manifestations in transgenic mice correlate with specific gut microbiome state. J. Alzheimers Dis. 56, 385–390 (2017).
Pistollato, F. et al. Role of gut microbiota and nutrients in amyloid formation and pathogenesis of Alzheimer disease. Nutr. Rev. 74, 624–634 (2016).
Berezov, T. T., Kudinova, N. V. & Kudinov, A. P. The role of Alzheimer amyloid plaques in the mechanisms of neuron synaptic plasticity disturbance. Vestn. Ross. Akad. Med. Nauk. 60, 3–7 (2005).
Akbari, E. et al. Effect of probiotic supplementation on cognitive function and metabolic status in Alzheimer’s disease: a randomized, double-blind and controlled trial. Front. Aging Neurosci. 2016; 8, 256 (2016).
Bonfili, L. et al. SLAB51 probiotic formulation activates SIRT1 pathway promoting antioxidant and neuroprotective effects in an AD mouse model. Mol. Neurobiol. 55, 7987–8000 (2018).
Sun, J. et al. Clostridium butyricum attenuates chronic unpredictable mild stress-induced depressive-like behavior in mice via the gut-brain axis. J. Agric. Food Chem. 66, 8415–8421 (2018).
Liu, J. et al. Neuroprotective effects of Clostridium butyricum against vascular dementia in mice via metabolic butyrate. BioMed. Res. Int. 2015, 412946 (2015).
Sun, J. et al. Clostridium butyricum attenuates cerebral ischemia/reperfusion injury in diabetic mice via modulation of gut microbiota. Brain Res. 1642, 180–188 (2016).
Li, H. et al. Clostridium butyricum exerts a neuroprotective effect in a mouse model of traumatic brain injury via the gut-brain axis. Neurogastroenterol. Motil. 30, e13260 (2018).
Han, A., Sung, Y. B., Chung, S. Y. & Kwon, M. S. Possible additional antidepressant-like mechanism of sodium butyrate: targeting the hippocampus. Neuropharmacology 81, 292–302 (2014).
Schroeder, F. A., Lin, C. L., Crusio, W. E. & Akbarian, S. Antidepressant-like effects of the histone deacetylase inhibitor, sodium butyrate, in the mouse. Biol. Psychiatry 62, 55–64 (2007).
Liu, J. et al. Sodium butyrate exerts protective effect against Parkinson’s disease in mice via stimulation of glucagon like peptide-1. J. Neurol. Sci. 381, 176–181 (2017).
Sun, J. et al. Antidepressant-like effects of sodium butyrate and its possible mechanisms of action in mice exposed to chronic unpredictable mild stress. Neurosci. Lett. 618, 159–166 (2016).
Li, H. et al. Sodium butyrate exerts neuroprotective effects by restoring the blood-brain barrier in traumatic brain injury mice. Brain Res. 1642, 70–78 (2016).
Macfabe, D. F. Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders. Microb. Ecol. Health Dis. 23, 19260 (2012).
Macfarlane, S. & Macfarlane, G. T. Regulation of short-chain fatty acid production. Proc. Nutr. Soc. 62, 67–72 (2003).
Kang, D. et al. Microbiota Transfer Therapy alters gut ecosystem and improves gastrointestinal and autism symptoms: an open-label study. Microbiome 5, 10 (2017).
Xu, Z. et al. Fecal microbiota transplantation from healthy donors reduced alcohol-induced anxiety and depression in an animal model of chronic alcohol exposure. Chin. J. Physiol. 61, 360–371 (2018).
Yang, C. et al. Key role of gut microbiota in anhedonia-like phenotype in rodents with neuropathic pain. Transl. Psychiatry 9, 57 (2019).
Sun, M. et al. Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: gut microbiota, glial reaction and TLR4/TNF-α signaling pathway. Brain, Behav., Immun. 70, 48–60 (2018).
Wei, Y. et al. Fecal microbiota transplantation ameliorates experimentally induced colitis in mice by upregulating AhR. Front. Microbiol. 9, 1921 (2018).
Suez, J. et al. Artificial sweeteners induce glucose intolerance by altering the gut microbiota. Nature 514, 181–186 (2014).
Wu, Y. Y., Hsu, C. M., Chen, P. H., Fung, C. P. & Chen, L. W. Toll-like receptor stimulation induces nondefensin protein expression and reverses antibiotic-induced gut defense impairment. Infect. Immun. 82, 1994–2005 (2014).
Zhou, D. et al. Total fecal microbiota transplantation alleviates high-fat diet-induced steatohepatitis in mice via beneficial regulation of gut microbiota. Sci. Rep. 7, 1529 (2017).
Zheng, H. et al. NMR-based metabolomics reveal a recovery from metabolic changes in the striatum of 6-OHDA-induced rats treated with basic fibroblast growth factor. Mol. Neurobiol. 53, 6690–6697 (2016).
Kim, T. K. et al. Analysis of differential plaque depositions in the brains of Tg2576 and Tg-APPswe/PS1dE9 transgenic mouse models of Alzheimer disease. Exp. Mol. Med. 44, 492–502 (2012).
Xin, Y. et al. Effects of oligosaccharides from Morinda officinalis on gut microbiota and metabolome of APP/PS1 transgenic mice. Front Neurol. 9, 412 (2018).
Sun, J. et al. Liraglutide improves water Maze learning and memory performance while reduces hyperphosphorylation of tau and neurofilaments in APP/PS1/Tau triple transgenic mice. Neurochem. Res. 42, 2326–2335 (2017).
Mancuso, C. & Santangelo, R. Alzheimer’s disease and gut microbiota modifications: the long way between preclinical studies and clinical evidence. Pharmacol. Res. 129, 329–336 (2018).
Nimgampalle, M. & Kuna, Y. Anti-Alzheimer properties of probiotic, Lactobacillus plantarum MTCC 1325 in Alzheimer’s disease induced albino rats. J. Clin. Diagn. Res. 11, KC01–KC05 (2017).
Wang, D. et al. beta2 adrenergic receptor, protein kinase A (PKA) and c-Jun N-terminal kinase (JNK) signaling pathways mediate tau pathology in Alzheimer disease models. J. Biol. Chem. 288, 10298–10307 (2013).
Yao, Z., Yang, W., Gao, Z. & Jia, P. Nicotinamide mononucleotide inhibits JNK activation to reverse Alzheimer disease. Neurosci. Lett. 647, 133–140 (2017).
Ramin, M., Azizi, P., Motamedi, F., Haghparast, A. & Khodagholi, F. Inhibition of JNK phosphorylation reverses memory deficit induced by beta-amyloid (1-42) associated with decrease of apoptotic factors. Behav. Brain Res. 217, 424–431 (2011).
Cisse, M. et al. The transcription factor XBP1s restores hippocampal synaptic plasticity and memory by control of the Kalirin-7 pathway in Alzheimer model. Mol. Psychiatry 22, 1562–1575 (2017).
Koss, D. J., Drever, B. D., Stoppelkamp, S., Riedel, G. & Platt, B. Age-dependent changes in hippocampal synaptic transmission and plasticity in the PLB1 Triple Alzheimer mouse. Cell Mol. Life Sci. 70, 2585–2601 (2013).
Sultana, R., Banks, W. A. & Butterfield, D. A. Decreased levels of PSD95 and two associated proteins and increased levels of BCl2 and caspase 3 in hippocampus from subjects with amnestic mild cognitive impairment: insights into their potential roles for loss of synapses and memory, accumulation of Abet. J. Neurosci. Res. 88, 469–477 (2010).
Benarroch, E. E. Glutamatergic synaptic plasticity and dysfunction in Alzheimer disease: emerging mechanisms. Neurology 91, 125–132 (2018).
Skaper, S. D., Facci, L., Zusso, M. & Giusti, P. Synaptic plasticity, dementia and Alzheimer disease. CNS Neurol. Disord. Drug Targets 16, 220–233 (2017).
Shankar, G. M. et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat. Med. 14, 837–842 (2008).
Piserchio, A., Spaller, M. & Mierke, D. F. Targeting the PDZ domains of molecular scaffolds of transmembrane ion channels. AAPS J. 8, E396–E401 (2006).
Marsh, J., Bagol, S. H., Williams, R. S. B., Dickson, G. & Alifragis, P. Synapsin I phosphorylation is dysregulated by beta-amyloid oligomers and restored by valproic acid. Neurobiol. Dis. 106, 63–75 (2017).
Larson, M. E. et al. Selective lowering of synapsins induced by oligomeric alpha-synuclein exacerbates memory deficits. Proc. Natl Acad. Sci. USA 114, E4648–E4657 (2017).
Woo, J. Y. et al. Lactobacillus pentosus var. plantarum C29 ameliorates memory impairment and inflammaging in a D-galactose-induced accelerated aging mouse model. Anaerobe 27, 22–26 (2014).
Aïd, S. & Bosetti, F. Targeting cyclooxygenases-1 and -2 in neuroinflammation: therapeutic implications. Biochimie 93, 46–51 (2011).
Petrov, V. et al. Analysis of gut microbiota in patients with Parkinson’s disease. Bull. Exp. Biol. Med. 162, 734–737 (2017).
Scheperjans, F. et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov. Disord. 30, 350–358 (2015).
Zhang, L. et al. Altered gut microbiota in a mouse model of Alzheimer’s disease. J. Alzheimers Dis. 60, 1241–1257 (2017).
Cattaneo, A. et al. Association of brain amyloidosis with pro-inflammatory gut bacterial taxa and peripheral inflammation markers in cognitively impaired elderly. Neurobiol. Aging 49, 60–68 (2017).
Minter, M. R. et al. Antibiotic-induced perturbations in microbial diversity during post-natal development alters amyloid pathology in an aged APPSWE/PS1 ΔE9 murine model of Alzheimer’s disease. Sci. Rep. 7, 10411 (2017).
OR, J. A. et al. Modulation of intestinal microbiota by the probiotic VSL#3 resets brain gene expression and ameliorates the age-related deficit in LTP. PloS ONE 9, e106503 (2014).
Biagi, E. et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS ONE 5, e10667 (2010).
Bauerl, C., Collado, M. C., Diaz Cuevas, A., Vina, J. & Perez Martinez, G. Shifts in gut microbiota composition in an APP/PSS1 transgenic mouse model of Alzheimer’s disease during lifespan. Lett. Appl. Microbiol. 66, 464–471 (2018).
Shin, N. R., Whon, T. W. & Bae, J. W. Proteobacteria: microbial signature of dysbiosis in gut microbiota. Trends Biotechnol. 33, 496–503 (2015).
Chen, C. H., Lin, C. L. & Kao, C. H. Irritable bowel syndrome Is associated with an increased risk of dementia: a nationwide population-based study. PLoS ONE 11, e0144589 (2016).
Wang, J. et al. The effects of LW-AFC on intestinal microbiome in senescence-accelerated mouse prone 8 strain, a mouse model of Alzheimer’s disease. J. Alzheimers Dis. 53, 907–919 (2016).
Malkki, H. Parkinson disease: Could gut microbiota influence severity of Parkinson disease? Nat. Rev. Neurol. 13, 66–67 (2017).
Debelius, J. et al. Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov. Disord. 32, 739–749 (2017).
Pandey, U. et al. The nasal and gut microbiome in Parkinson’s disease and idiopathic rapid eye movement sleep behavior disorder. Mov. Disord. 33, 88–98 (2018).
Harach, T. et al. Erratum: Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci. Rep. 7, (46856 (2017).
Brandscheid, C. et al. Altered gut microbiome composition and tryptic activity of the 5xFAD Alzheimer’s mouse model. J. Alzheimers Dis. 56, 775–788 (2017).
He, Y. et al. Gut microbiome and magnetic resonance spectroscopy study of subjects at ultra-high risk for psychosis may support the membrane hypothesis. Eur. Psychiat. 53, 37–45 (2018).
Varela, R. B. et al. Sodium butyrate and mood stabilizers block ouabain-induced hyperlocomotion and increase BDNF, NGF and GDNF levels in brain of Wistar rats. J. Psychiatr. Res. 61, 114–121 (2015).
Erny, D. et al. Host microbiota constantly control maturation and function of microglia in the CNS. Nat. Neurosci. 18, 965–977 (2015).
MacFabe, D. F. et al. Neurobiological effects of intraventricular propionic acid in rats: possible role of short chain fatty acids on the pathogenesis and characteristics of autism spectrum disorders. Behav. Brain Res. 176, 149–169 (2007).
Ho, L. et al. Protective roles of intestinal microbiota derived short chain fatty acids in Alzheimer’s disease-type beta-amyloid neuropathological mechanisms. Expert Rev. Neurother. 18, 83–90 (2018).
Griseri, P. et al. Rescue of human RET gene expression by sodium butyrate: a novel powerful tool for molecular studies in Hirschsprung disease. Gut 52, 1154–1158 (2003).
Sun, J. et al. Neuroprotective effect of sodium butyrate against cerebral ischemia/reperfusion injury in mice. BioMed. Res. Int. 2015, 395895 (2015).