Abstract
A growing body of evidence implies that gut microbiota was involved in pathogenesis of Parkinson’s disease (PD), but the mechanism is still unclear. The aim of this study is to investigate the effects of antibiotics pretreatment on the 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced PD mice. In this study, vancomycin pretreatment was given by gavage once daily with either vancomycin or distilled water for 14 days to mice, then mice were administered with MPTP (20 mg/kg, i.p) for four times in one day to establish an acute PD model. Results show that vancomycin pretreatment significantly improved motor dysfunction of mice in pole and traction tests. Although vancomycin pretreatment had no effect on dopamine (DA) or the process of DA synthesis, it inhibited the metabolism of DA by suppressing the expression of striatal monoamine oxidase B (MAO-B). Furthermore, vancomycin pretreatment reduced the number of astrocytes and microglial cells in the substantia nigra pars compacta (SNpc) to alleviate neuroinflammation, decreased the expression of TLR4/MyD88/NF-κB/TNF-α signaling pathway in both brain and gut. Meanwhile, vancomycin pretreatment changed gut microbiome composition and the levels of fecal short chain fatty acids (SCFAs). The abundance of Akkermansia and Blautia increased significantly after vancomycin pretreatment, which might be related to inflammation and inhibition of TLR4 signaling pathway. In summary, these results demonstrate that the variation of gut microbiota and its metabolites induced by vancomycin pretreatment might decrease dopamine metabolic rate and relieve inflammation in both gut and brain via the microbiota-gut-brain axis in MPTP-induced PD mice.
Graphical Abstract
The neuroprotection of vancomycin pretreatment on MPTP-induced Parkinson's disease mice
The alterations of gut microbiota and SCFAs induced by vancomycin pretreatment might not only improve motor dysfunction, but also decrease dopamine metabolism and relieve inflammation in both brain and gut via TLR4/MyD88/NF-κB/TNF-α pathway in MPTP-induced PD mice.
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References
Aho VTE, Houser MC, Pereira PAB, Chang J, Rudi K, Paulin L, Hertzberg V, Auvinen P, Tansey MG, Scheperjans F (2021) Relationships of gut microbiota, short-chain fatty acids, inflammation, and the gut barrier in Parkinson’s disease. Mol Neurodegener 16:6. https://doi.org/10.1186/s13024-021-00427-6
Alborghetti M, Nicoletti F (2019) Different generations of Type-B monoamine oxidase inhibitors in Parkinson’s disease: From bench to bedside. Curr Neuropharmacol 17:861–873. https://doi.org/10.2174/1570159X16666180830100754
Atarashi K et al (2013) Treg induction by a rationally selected mixture of Clostridia strains from the human microbiota. Nature 500:232–236. https://doi.org/10.1038/nature12331
Bai YF, Wang SW, Wang XX, Weng YY, Fan XY, Sheng H, Zhu XT, Lou LJ, Zhang F (2019) The flavonoid-rich Quzhou Fructus Aurantii extract modulates gut microbiota and prevents obesity in high-fat diet-fed mice. Nutr Diabetes 9:30. https://doi.org/10.1038/s41387-019-0097-6
Benitez-Paez A, Gomez Del Pugar EM, Lopez-Almela I, Moya-Perez A, Codoner-Franch P, Sanz Y (2020) Depletion of Blautia species in the microbiota of obese children relates to intestinal inflammation and metabolic phenotype worsening. mSystems 5. https://doi.org/10.1128/mSystems.00857-19
Bian X, Wu W, Yang L, Lv L, Wang Q, Li Y, Ye J, Fang D, Wu J, Jiang X, Shi D, Li L (2019) Administration of Akkermansia muciniphila ameliorates dextran sulfate sodium-induced ulcerative colitis in mice. Front Microbiol 10:2259. https://doi.org/10.3389/fmicb.2019.02259
Carradori S, Silvestri R (2015) New frontiers in selective human MAO-B inhibitors. J Med Chem 58:6717–6732. https://doi.org/10.1021/jm501690r
Chen Y, Zhao S, Jiao D, Yao B, Yang S, Li P, Long M (2021) Astaxanthin alleviates ochratoxin A-induced cecum injury and inflammation in mice by regulating the diversity of cecal microbiota and TLR4/MyD88/NF-kappaB signaling pathway. Oxid Med Cell Longev 2021:8894491. https://doi.org/10.1155/2021/8894491
Chun H et al (2020) Severe reactive astrocytes precipitate pathological hallmarks of Alzheimer’s disease via H2O2(-) production. Nat Neurosci 23:1555–1566. https://doi.org/10.1038/s41593-020-00735-y
Cirstea MS, Yu AC, Golz E, Sundvick K, Kliger D, Radisavljevic N, Foulger LH, Mackenzie M, Huan T, Finlay BB, Appel-Cresswell S (2020) Microbiota composition and metabolism are associated with gut function in Parkinson’s disease. Mov Disord 35:1208–1217. https://doi.org/10.1002/mds.28052
Devos D, Lebouvier T, Lardeux B, Biraud M, Rouaud T, Pouclet H, Coron E, des Varannes SB, Naveilhan P, Nguyen JM, Neunlist M, Derkinderen P (2013) Colonic inflammation in Parkinson’s disease. Neurobiol Dis 50:42–48. https://doi.org/10.1016/j.nbd.2012.09.007
Edgar RC (2013) UPARSE: Highly accurate OTU sequences from microbial amplicon reads. Nat Methods 10:996–998. https://doi.org/10.1038/nmeth.2604
Everard A, Belzer C, Geurts L, Ouwerkerk JP, Druart C, Bindels LB, Guiot Y, Derrien M, Muccioli GG, Delzenne NM, de Vos WM, Cani PD (2013) Cross-talk between Akkermansia muciniphila and intestinal epithelium controls diet-induced obesity. Proc Natl Acad Sci USA 110:9066–9071. https://doi.org/10.1073/pnas.1219451110
Franzosa EA et al (2019) Gut microbiome structure and metabolic activity in inflammatory bowel disease. Nat Microbiol 4:293–305. https://doi.org/10.1038/s41564-018-0306-4
Fu X, Liu Z, Zhu C, Mou H, Kong Q (2019) Nondigestible carbohydrates, butyrate, and butyrate-producing bacteria. Crit Rev Food Sci Nutr 59:S130–S152. https://doi.org/10.1080/10408398.2018.1542587
Gao H, Shu Q, Chen J, Fan K, Xu P, Zhou Q, Li C, Zheng H (2019) Antibiotic exposure has sex-dependent effects on the gut microbiota and metabolism of short-chain fatty acids and amino acids in mice. mSystems 4. https://doi.org/10.1128/mSystems.00048-19
Garcia-Dominguez I, Vesela K, Garcia-Revilla J, Carrillo-Jimenez A, Roca-Ceballos MA, Santiago M, de Pablos RM, Venero JL (2018) Peripheral inflammation enhances microglia response and nigral dopaminergic cell death in an in vivo MPTP model of Parkinson’s disease. Front Cell Neurosci 12:398. https://doi.org/10.3389/fncel.2018.00398
Kim MH, Kang SG, Park JH, Yanagisawa M, Kim CH (2013) Short-chain fatty acids activate GPR41 and GPR43 on intestinal epithelial cells to promote inflammatory responses in mice. Gastroenterology 145(396–406):e391–e310. https://doi.org/10.1053/j.gastro.2013.04.056
Koutzoumis DN, Vergara M, Pino J, Buddendorff J, Khoshbouei H, Mandel RJ, Torres GE (2020) Alterations of the gut microbiota with antibiotics protects dopamine neuron loss and improve motor deficits in a pharmacological rodent model of Parkinson’s disease. Exp Neurol 325:113159. https://doi.org/10.1016/j.expneurol.2019.113159
Kuter KZ, Olech L, Glowacka U, Paleczna M (2021) Increased beta-hydroxybutyrate level is not sufficient for the neuroprotective effect of long-term ketogenic diet in an animal model of early Parkinson’s disease. Exploration of brain and liver energy metabolism markers. Int J Mol Sci 22. https://doi.org/10.3390/ijms22147556
Lee J, d’Aigle J, Atadja L, Quaicoe V, Honarpisheh P, Ganesh BP, Hassan A, Graf J, Petrosino J, Putluri N, Zhu L, Durgan DJ, Bryan RM Jr, McCullough LD, Venna VR (2020) Gut microbiota-derived short-chain fatty acids promote poststroke recovery in aged mice. Circ Res 127:453–465. https://doi.org/10.1161/CIRCRESAHA.119.316448
Levitt P, Pintar JE, Breakefield XO (1982) Immunocytochemical demonstration of monoamine oxidase B in brain astrocytes and serotonergic neurons. Proc Natl Acad Sci USA 79:6385–6389. https://doi.org/10.1073/pnas.79.20.6385
Li W, Wu X, Hu X, Wang T, Liang S, Duan Y, Jin F, Qin B (2017) Structural changes of gut microbiota in Parkinson’s disease and its correlation with clinical features. Sci China Life Sci 60:1223–1233. https://doi.org/10.1007/s11427-016-9001-4
Lucas K, Maes M (2013) Role of the toll like receptor (TLR) radical cycle in chronic inflammation: Possible treatments targeting the TLR4 pathway. Mol Neurobiol 48:190–204. https://doi.org/10.1007/s12035-013-8425-7
Nakanishi Y, Sato T, Ohteki T (2015) Commensal gram-positive bacteria initiates colitis by inducing monocyte/macrophage mobilization. Mucosal Immunol 8:152–160. https://doi.org/10.1038/mi.2014.53
Norden DM, Trojanowski PJ, Walker FR, Godbout JP (2016) Insensitivity of astrocytes to interleukin 10 signaling following peripheral immune challenge results in prolonged microglial activation in the aged brain. Neurobiol Aging 44:22–41. https://doi.org/10.1016/j.neurobiolaging.2016.04.014
Ondov BD, Bergman NH, Phillippy AM (2011) Interactive metagenomic visualization in a web browser. BMC Bioinformatics 12:385. https://doi.org/10.1186/1471-2105-12-385
Park JH, Kotani T, Konno T, Setiawan J, Kitamura Y, Imada S, Usui Y, Hatano N, Shinohara M, Saito Y, Murata Y, Matozaki T (2016) Promotion of intestinal epithelial cell turnover by commensal bacteria: Role of short-chain fatty acids. PLoS One 11:e0156334. https://doi.org/10.1371/journal.pone.0156334
Perez-Pardo P, Dodiya HB, Engen PA, Forsyth CB, Huschens AM, Shaikh M, Voigt RM, Naqib A, Green SJ, Kordower JH, Shannon KM, Garssen J, Kraneveld AD, 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
Pruesse E, Quast C, Knittel K, Fuchs BM, Ludwig W, Peplies J, Glockner FO (2007) SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB. Nucleic Acids Res 35:7188–7196. https://doi.org/10.1093/nar/gkm864
Pu Y, Chang L, Qu Y, Wang S, Zhang K, Hashimoto K (2019) Antibiotic-induced microbiome depletion protects against MPTP-induced dopaminergic neurotoxicity in the brain. Aging (Albany NY) 11:6915–6929. https://doi.org/10.18632/aging.102221
Rajpal DK, Klein JL, Mayhew D, Boucheron J, Spivak AT, Kumar V, Ingraham K, Paulik M, Chen L, Van Horn S, Thomas E, Sathe G, Livi GP, Holmes DJ, Brown JR (2015) Selective spectrum antibiotic modulation of the gut microbiome in obesity and diabetes rodent models. PLoS One 10:e0145499. https://doi.org/10.1371/journal.pone.0145499
Rauhamaki S, Postila PA, Niinivehmas S, Kortet S, Schildt E, Pasanen M, Manivannan E, Ahinko M, Koskimies P, Nyberg N, Huuskonen P, Multamaki E, Pasanen M, Juvonen RO, Raunio H, Huuskonen J, Pentikainen OT (2018) Structure-activity relationship analysis of 3-phenylcoumarin-based monoamine oxidase B inhibitors. Front Chem 6:41. https://doi.org/10.3389/fchem.2018.00041
Ring C, Klopfleisch R, Dahlke K, Basic M, Bleich A, Blaut M (2019) Akkermansia muciniphila strain ATCC BAA-835 does not promote short-term intestinal inflammation in gnotobiotic interleukin-10-deficient mice. Gut Microbes 10:188–203. https://doi.org/10.1080/19490976.2018.1511663
Rooks MG, Garrett WS (2016) Gut microbiota, metabolites, and host immunity. Nat Rev Immunol 16:341–352. https://doi.org/10.1038/nri.2016.42
Rostami J, Fotaki G, Sirois J, Mzezewa R, Bergstrom J, Essand M, Healy L, Erlandsson A (2020) Astrocytes have the capacity to act as antigen-presenting cells in the Parkinson’s disease brain. J Neuroinflammation 17:119. https://doi.org/10.1186/s12974-020-01776-7
Samii A, Nutt JG, Ransom BR (2004) Parkinson’s disease. Lancet 363:1783–1793. https://doi.org/10.1016/S0140-6736(04)16305-8
Sampson TR, Debelius JW, Thron T, Janssen S, Shastri GG, Ilhan ZE, Challis C, Schretter CE, Rocha S, Gradinaru V, Chesselet MF, Keshavarzian A, Shannon KM, Krajmalnik-Brown R, Wittung-Stafshede P, Knight R, Mazmanian SK (2016) Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 167(1469–1480):e1412. https://doi.org/10.1016/j.cell.2016.11.018
Scheperjans F, Aho V, Pereira PA, Koskinen K, Paulin L, Pekkonen E, Haapaniemi E, Kaakkola S, Eerola-Rautio J, Pohja M, Kinnunen E, Murros K, Auvinen P (2015) Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord 30:350–358. https://doi.org/10.1002/mds.26069
Shao QH, Chen Y, Li FF, Wang S, Zhang XL, Yuan YH, Chen NH (2019) TLR4 deficiency has a protective effect in the MPTP/probenecid mouse model of Parkinson’s disease. Acta Pharmacol Sin 40:1503–1512. https://doi.org/10.1038/s41401-019-0280-2
Sharma A, Liaw K, Sharma R, Zhang Z, Kannan S, Kannan RM (2018) Targeting mitochondrial dysfunction and oxidative stress in activated microglia using dendrimer-based therapeutics. Theranostics 8:5529–5547. https://doi.org/10.7150/thno.29039
Sheng K, Zhang G, Sun M, He S, Kong X, Wang J, Zhu F, Zha X, Wang Y (2020) Grape seed proanthocyanidin extract ameliorates dextran sulfate sodium-induced colitis through intestinal barrier improvement, oxidative stress reduction, and inflammatory cytokines and gut microbiota modulation. Food Funct 11:7817–7829. https://doi.org/10.1039/d0fo01418d
Sina C, Gavrilova O, Forster M, Till A, Derer S, Hildebrand F, Raabe B, Chalaris A, Scheller J, Rehmann A, Franke A, Ott S, Hasler R, Nikolaus S, Folsch UR, Rose-John S, Jiang HP, Li J, Schreiber S, Rosenstiel P (2009) G protein-coupled receptor 43 is essential for neutrophil recruitment during intestinal inflammation. J Immunol 183:7514–7522. https://doi.org/10.4049/jimmunol.0900063
Singh S, Moudgil A, Mishra N, Das S, Mishra P (2019) Vancomycin functionalized WO3 thin film-based impedance sensor for efficient capture and highly selective detection of Gram-positive bacteria. Biosens Bioelectron 136:23–30. https://doi.org/10.1016/j.bios.2019.04.029
Soto M, Herzog C, Pacheco JA, Fujisaka S, Bullock K, Clish CB, Kahn CR (2018) Gut microbiota modulate neurobehavior through changes in brain insulin sensitivity and metabolism. Mol Psychiatry 23:2287–2301. https://doi.org/10.1038/s41380-018-0086-5
Stefano GB, Pilonis N, Ptacek R, Raboch J, Vnukova M, Kream RM (2018) Gut, Microbiome, and brain regulatory axis: Relevance to neurodegenerative and psychiatric disorders. Cell Mol Neurobiol 38:1197–1206. https://doi.org/10.1007/s10571-018-0589-2
Sun F, Liu F (2020) Platycodin D inhibits MPP(+)-induced inflammatory response in BV-2 cells through the TLR4/MyD88/NF-kappaB signaling pathway. J Recept Signal Transduct Res 40:479–485. https://doi.org/10.1080/10799893.2020.1767135
Sun MF, Zhu YL, Zhou ZL, Jia XB, Xu YD, Yang Q, Cui C, Shen YQ (2018) Neuroprotective effects of fecal microbiota transplantation on MPTP-induced Parkinson’s disease mice: Gut microbiota, glial reaction and TLR4/TNF-alpha signaling pathway. Brain Behav Immun 70:48–60. https://doi.org/10.1016/j.bbi.2018.02.005
Tran SM, Mohajeri MH (2021) The role of gut bacterial metabolites in brain development aging and disease. Nutrients 13. https://doi.org/10.3390/nu13030732
Unger MM, Spiegel J, Dillmann KU, Grundmann D, Philippeit H, Burmann J, Fassbender K, Schwiertz A, Schafer KH (2016) Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord 32:66–72. https://doi.org/10.1016/j.parkreldis.2016.08.019
Uribe-Herranz M, Rafail S, Beghi S, Gil-de-Gomez L, Verginadis I, Bittinger K, Pustylnikov S, Pierini S, Perales-Linares R, Blair IA, Mesaros CA, Snyder NW, Bushman F, Koumenis C, Facciabene A (2020) Gut microbiota modulate dendritic cell antigen presentation and radiotherapy-induced antitumor immune response. J Clin Invest 130:466–479. https://doi.org/10.1172/JCI124332
Van den Abbeele P, Belzer C, Goossens M, Kleerebezem M, De Vos WM, Thas O, De Weirdt R, Kerckhof FM, Van de Wiele T (2013) Butyrate-producing Clostridium cluster XIVa species specifically colonize mucins in an in vitro gut model. ISME J 7:949–961. https://doi.org/10.1038/ismej.2012.158
Villumsen M, Aznar S, Pakkenberg B, Jess T, Brudek T (2019) Inflammatory bowel disease increases the risk of Parkinson’s disease: a Danish nationwide cohort study 1977–2014. Gut 68:18–24. https://doi.org/10.1136/gutjnl-2017-315666
Wang L, Yu K, Zhang X, Yu S (2018) Dual functional roles of the MyD88 signaling in colorectal cancer development. Biomed Pharmacother 107:177–184. https://doi.org/10.1016/j.biopha.2018.07.139
Wang Q, Liu Y, Zhou J (2015) Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Transl Neurodegener 4:19. https://doi.org/10.1186/s40035-015-0042-0
Wang Q, Garrity GM, Tiedje JM, Cole JR (2007) Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol 73:5261–5267. https://doi.org/10.1128/AEM.00062-07
Yang Y, Zhong Z, Wang B, Xia X, Yao W, Huang L, Wang Y, Ding W (2019) Early-life high-fat diet-induced obesity programs hippocampal development and cognitive functions via regulation of gut commensal Akkermansia muciniphila. Neuropsychopharmacology 44:2054–2064. https://doi.org/10.1038/s41386-019-0437-1
Yap IK, Li JV, Saric J, Martin FP, Davies H, Wang Y, Wilson ID, Nicholson JK, Utzinger J, Marchesi JR, Holmes E (2008) Metabonomic and microbiological analysis of the dynamic effect of vancomycin-induced gut microbiota modification in the mouse. J Proteome Res 7:3718–3728. https://doi.org/10.1021/pr700864x
Zhong Z, Chen W, Gao H, Che N, Xu M, Yang L, Zhang Y, Ye M (2021) Fecal microbiota transplantation exerts a protective role in MPTP-induced Parkinson’s disease via the TLR4/PI3K/AKT/NF-kappaB pathway stimulated by alpha-synuclein. Neurochem Res 46:3050–3058. https://doi.org/10.1007/s11064-021-03411-0
Zhou ZL, Jia XB, Sun MF, Zhu YL, Qiao CM, Zhang BP, Zhao LP, Yang Q, Cui C, Chen X, Shen YQ (2019) Neuroprotection of fasting mimicking diet on MPTP-induced Parkinson’s disease mice via gut microbiota and metabolites. Neurotherapeutics 16:741–760. https://doi.org/10.1007/s13311-019-00719-2
Funding
This study was supported by National Natural Science Foundation of China (82171429, 81771384, 81801276), Wuxi Municipal Health Commission (1286010241190480), Youth Foundation of Basic Research Program of Jiangnan University (JUSRP121063).
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The experiment design: Chun Cui, Hui Hong, Yan-Qin Shen; Establishment of MPTP model: Hui Hong, Yun Shi; Immunofluorescence and image analysis: Hui Hong, Chun Cui, Wei-Jiang Zhao, Wei Quan, Gu-Yu Niu; Behavioral test and feces collection: Hui Hong, Yu Zhou, Yun Shi; Western blot analysis and Enzyme-linked immunosorbent assay: Hui Hong, Wei Quan, Gu-Yu Niu, Yi-Bo Wu; Measurement of neurotransmitters and their metabolites and Analysis of short chain fatty acids in feces: Hui Hong, Yun Shi, Li-Ping Zhao, Yu Zhou, Chao-Sheng Li, Li Cheng; Statistical analysis: Chun Cui, Hui Hong, Jian Wu, Yan Hong; Interpretation and editing of manuscript: Chun Cui, Hui Hong, Yan-Qin Shen.
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Cui, C., Hong, H., Shi, Y. et al. Vancomycin Pretreatment on MPTP-Induced Parkinson’s Disease Mice Exerts Neuroprotection by Suppressing Inflammation Both in Brain and Gut. J Neuroimmune Pharmacol 18, 72–89 (2023). https://doi.org/10.1007/s11481-021-10047-y
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DOI: https://doi.org/10.1007/s11481-021-10047-y