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Intestinal Pathology and Gut Microbiota Alterations in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Mouse Model of Parkinson’s Disease

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Abstract

Patients with Parkinson’s disease (PD) often have non-motor symptoms related to gastrointestinal (GI) dysfunction, such as constipation and delayed gastric emptying, which manifest prior to the motor symptoms of PD. Increasing evidence indicates that changes in the composition of the gut microbiota may be related to the pathogenesis of PD. However, it is unclear how GI dysfunction occurs and how gut microbial dysbiosis is caused. We investigated whether a neurotoxin model of PD induced by chronic low doses of MPTP is capable of reproducing the clinical intestinal pathology of PD, as well as whether gut microbial dysbiosis accompanies this pathology. C57BL/6 male mice were administered 18 mg/kg MPTP twice per week for 5 weeks via intraperitoneal injection. GI function was assessed by measuring the 1-h stool frequency and fecal water content; motor function was assessed by pole tests; and tyrosine hydroxylase and alpha-synuclein expression were analyzed. Furthermore, the inflammation, intestinal barrier and composition of the gut microbiota were measured. We found that MPTP caused GI dysfunction and intestinal pathology prior to motor dysfunction. The composition of the gut microbiota was changed; in particular, the change in the abundance of Lachnospiraceae, Erysipelotrichaceae, Prevotellaceae, Clostridiales, Erysipelotrichales and Proteobacteria was significant. These results indicate that a chronic low-dose MPTP model can be used to evaluate the progression of intestinal pathology and gut microbiota dysbiosis in the early stage of PD, which may provide new insights into the pathogenesis of PD.

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References

  1. Dickson DW (2018) Neuropathology of Parkinson disease. Parkinsonism Relat Disord 46(Suppl 1):S30–S33. https://doi.org/10.1016/j.parkreldis.2017.07.033

    Article  PubMed  Google Scholar 

  2. Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386(9996):896–912. https://doi.org/10.1016/s0140-6736(14)61393-3

    Article  CAS  PubMed  Google Scholar 

  3. Hussl A, Seppi K, Poewe W (2013) Nonmotor symptoms in Parkinson’s disease. Expert Rev Neurother 13(6):581–583. https://doi.org/10.1586/ern.13.53

    Article  CAS  PubMed  Google Scholar 

  4. Fasano A, Visanji NP, Li LWC, Lang AE, Pfeiffer RF (2015) Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 14(6):625–639. https://doi.org/10.1016/s1474-4422(15)00007-1

    Article  CAS  PubMed  Google Scholar 

  5. Clairembault T, Leclair-Visonneau L, Coron E, Bourreille A, Le Dily S, Vavasseur F, Heymann MF, Neunlist M, Derkinderen P (2015) Structural alterations of the intestinal epithelial barrier in Parkinson’s disease. Acta Neuropathol Commun 3:12. https://doi.org/10.1186/s40478-015-0196-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 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(3):350–358. https://doi.org/10.1002/mds.26069

    Article  PubMed  Google Scholar 

  7. Braak H, Rub U, Gai WP, Del Tredici K (2003) Idiopathic Parkinson’s disease: possible routes by which vulnerable neuronal types may be subject to neuroinvasion by an unknown pathogen. J Neural Transm 110(5):517–536. https://doi.org/10.1007/s00702-002-0808-2

    Article  CAS  PubMed  Google Scholar 

  8. Braak H, de Vos RA, Bohl J, Del Tredici K (2006) Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 396(1):67–72. https://doi.org/10.1016/j.neulet.2005.11.012

    Article  CAS  PubMed  Google Scholar 

  9. Phillips RJ, Walter GC, Wilder SL, Baronowsky EA, Powley TL (2008) Alpha-synuclein-immunopositive myenteric neurons and vagal preganglionic terminals: autonomic pathway implicated in Parkinson’s disease? Neuroscience 153(3):733–750. https://doi.org/10.1016/j.neuroscience.2008.02.074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Anderson G, Noorian AR, Taylor G, Anitha M, Bernhard D, Srinivasan S, Greene JG (2007) Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson’s disease. Exp Neurol 207(1):4–12. https://doi.org/10.1016/j.expneurol.2007.05.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Natale G, Kastsiushenka O, Fulceri F, Ruggieri S, Paparelli A, Fornai F (2010) MPTP-induced parkinsonism extends to a subclass of TH-positive neurons in the gut. Brain Res 1355:195–206. https://doi.org/10.1016/j.brainres.2010.07.076

    Article  CAS  PubMed  Google Scholar 

  12. Poirier AA, Cote M, Bourque M, Morissette M, Di Paolo T, Soulet D (2016) Neuroprotective and immunomodulatory effects of raloxifene in the myenteric plexus of a mouse model of Parkinson’s disease. Neurobiol Aging 48:61–71. https://doi.org/10.1016/j.neurobiolaging.2016.08.004

    Article  CAS  PubMed  Google Scholar 

  13. Martin CR, Osadchiy V, Kalani A, Mayer EA (2018) The brain-gut-microbiome axis. Cell Mol Gastroenterol Hepatol. https://doi.org/10.1016/j.jcmgh.2018.04.003

    Article  PubMed  PubMed Central  Google Scholar 

  14. Foster JA, McVey Neufeld KA (2013) Gut-brain axis: how the microbiome influences anxiety and depression. Trends Neurosci 36(5):305–312. https://doi.org/10.1016/j.tins.2013.01.005

    Article  CAS  PubMed  Google Scholar 

  15. Vuong HE, Hsiao EY (2017) Emerging roles for the gut microbiome in autism spectrum disorder. Biol Psychiatry 81(5):411–423. https://doi.org/10.1016/j.biopsych.2016.08.024

    Article  PubMed  Google Scholar 

  16. Mancuso C, Santangelo R (2018) Alzheimer’s disease and gut microbiota modifications: the long way between preclinical studies and clinical evidence. Pharmacol Res 129:329–336. https://doi.org/10.1016/j.phrs.2017.12.009

    Article  CAS  PubMed  Google Scholar 

  17. 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

    Article  PubMed  Google Scholar 

  18. Hirsch EC, Vyas S, Hunot S (2012) Neuroinflammation in Parkinson’s disease. Parkinsonism Relat Disord 18:S210–S212. https://doi.org/10.1016/s1353-8020(11)70065-7

    Article  PubMed  Google Scholar 

  19. Sawada M, Imamura K, Nagatsu T (2006) Role of cytokines in inflammatory process in Parkinson’s disease. J Neural Transm Suppl 70:373–381

    Article  CAS  Google Scholar 

  20. Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S (1998) Microglia-specific localisation of a novel calcium binding protein, Iba1. Brain Res Mol Brain Res 57(1):1–9

    Article  CAS  PubMed  Google Scholar 

  21. Imai Y, Kohsaka S (2002) Intracellular signaling in M-CSF-induced microglia activation: role of Iba1. Glia 40(2):164–174. https://doi.org/10.1002/glia.10149

    Article  PubMed  Google Scholar 

  22. Hisahara S, Shimohama S (2010) Toxin-induced and genetic animal models of Parkinson’s disease. Parkinson’s Dis 2011:951709. https://doi.org/10.4061/2011/951709

    Article  CAS  Google Scholar 

  23. Nicotra A, Parvez SH (2000) Cell death induced by MPTP, a substrate for monoamine oxidase B. Toxicology 153(1–3):157–166

    Article  CAS  PubMed  Google Scholar 

  24. Perry TL, Yong VW, Jones K, Wall RA, Clavier RM, Foulks JG, Wright JM (1985) Effects of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and its metabolite, N-methyl-4-phenylpyridinium ion, on dopaminergic nigrostriatal neurons in the mouse. Neurosci Lett 58(3):321–326

    Article  CAS  PubMed  Google Scholar 

  25. Cote M, Drouin-Ouellet J, Cicchetti F, Soulet D (2011) The critical role of the MyD88-dependent pathway in non-CNS MPTP-mediated toxicity. Brain Behav Immun 25(6):1143–1152. https://doi.org/10.1016/j.bbi.2011.02.017

    Article  CAS  PubMed  Google Scholar 

  26. Xiao-Feng L, Wen-Ting Z, Yuan-Yuan X, Chong-Fa L, Lu Z, Jin-Jun R, Wen-Ya W (2016) Protective role of 6-hydroxy-1-H-indazole in an MPTP-induced mouse model of Parkinson’s disease. Eur J Pharmacol 791:348–354. https://doi.org/10.1016/j.ejphar.2016.08.011

    Article  CAS  PubMed  Google Scholar 

  27. Ellett LJ, Hung LW, Munckton R, Sherratt NA, Culvenor J, Grubman A, Furness JB, White AR, Finkelstein DI, Barnham KJ, Lawson VA (2016) Restoration of intestinal function in an MPTP model of Parkinson’s Disease. Sci Rep 6:30269. https://doi.org/10.1038/srep30269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lawson VA, Furness JB, Klemm HM, Pontell L, Chan E, Hill AF, Chiocchetti R (2010) The brain to gut pathway: a possible route of prion transmission. Gut 59(12):1643–1651. https://doi.org/10.1136/gut.2010.222620

    Article  CAS  PubMed  Google Scholar 

  29. Xu N, Tan G, Wang H, Gai X (2016) Effect of biochar additions to soil on nitrogen leaching, microbial biomass and bacterial community structure. Eur J Soil Biol 74:1–8. https://doi.org/10.1016/j.ejsobi.2016.02.004

    Article  CAS  Google Scholar 

  30. Cote M, Bourque M, Poirier AA, Aube B, Morissette M, Di Paolo T, Soulet D (2015) GPER1-mediated immunomodulation and neuroprotection in the myenteric plexus of a mouse model of Parkinson’s disease. Neurobiol Dis 82:99–113. https://doi.org/10.1016/j.nbd.2015.05.017

    Article  CAS  PubMed  Google Scholar 

  31. Ling Z, Jin C, Xie T, Cheng Y, Li L, Wu N (2016) Alterations in the fecal microbiota of patients with HIV-1 infection: an observational study in a Chinese population. Sci Rep 6:30673. https://doi.org/10.1038/srep30673

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Klingelhoefer L, Reichmann H (2015) Pathogenesis of Parkinson disease: the gut-brain axis and environmental factors. Nat Rev Neurol 11(11):625–636. https://doi.org/10.1038/nrneurol.2015.197

    Article  CAS  PubMed  Google Scholar 

  33. Munoz-Manchado AB, Villadiego J, Romo-Madero S, Suarez-Luna N, Bermejo-Navas A, Rodriguez-Gomez JA, Garrido-Gil P, Labandeira-Garcia JL, Echevarria M, Lopez-Barneo J, Toledo-Aral JJ (2016) Chronic and progressive Parkinson’s disease MPTP model in adult and aged mice. J Neurochem 136(2):373–387. https://doi.org/10.1111/jnc.13409

    Article  CAS  PubMed  Google Scholar 

  34. Duty S, Jenner P (2011) Animal models of Parkinson’s disease: a source of novel treatments and clues to the cause of the disease. Br J Pharmacol 164(4):1357–1391. https://doi.org/10.1111/j.1476-5381.2011.01426.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bezard E, Dovero S, Prunier C, Ravenscroft P, Chalon S, Guilloteau D, Crossman AR, Bioulac B, Brotchie JM, Gross CE (2001) Relationship between the appearance of symptoms and the level of nigrostriatal degeneration in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned macaque model of Parkinson’s disease. J Neurosci 21(17):6853–6861

    Article  CAS  PubMed  Google Scholar 

  36. Drolet RE, Cannon JR, Montero L, Greenamyre JT (2009) Chronic rotenone exposure reproduces Parkinson’s disease gastrointestinal neuropathology. Neurobiol Dis 36(1):96–102. https://doi.org/10.1016/j.nbd.2009.06.017

    Article  CAS  PubMed  Google Scholar 

  37. 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

    Article  CAS  PubMed  Google Scholar 

  38. 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(11):1223–1233. https://doi.org/10.1007/s11427-016-9001-4

    Article  PubMed  Google Scholar 

  39. Yang X, Qian Y, Xu S, Song Y, Xiao Q (2017) Longitudinal analysis of fecal microbiome and pathologic processes in a rotenone induced mice model of Parkinson’s disease. Front Aging Neurosci 9:441. https://doi.org/10.3389/fnagi.2017.00441

    Article  PubMed  Google Scholar 

  40. Hill-Burns EM, Debelius JW, Morton JT, Wissemann WT, Lewis MR, Wallen ZD, Peddada SD, Factor SA, Molho E, Zabetian CP, Knight R, Payami H (2017) Parkinson’s disease and Parkinson’s disease medications have distinct signatures of the gut microbiome. Mov Disord 32(5):739–749. https://doi.org/10.1002/mds.26942

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vizcarra JA, Wilson-Perez HE, Espay AJ (2015) The power in numbers: gut microbiota in Parkinson’s disease. Mov Disord 30(3):296–298. https://doi.org/10.1002/mds.26116

    Article  PubMed  Google Scholar 

  42. Antharam VC, Li EC, Ishmael A, Sharma A, Mai V, Rand KH, Wang GP (2013) Intestinal dysbiosis and depletion of butyrogenic bacteria in Clostridium difficile infection and nosocomial diarrhea. J Clin Microbiol 51(9):2884–2892. https://doi.org/10.1128/jcm.00845-13

    Article  PubMed  PubMed Central  Google Scholar 

  43. Biddle A, Stewart L, Blanchard J, Leschine S (2013) Untangling the genetic basis of fibrolytic specialization by Lachnospiraceae and Ruminococcaceae in diverse gut communities. Diversity 5(3):627–640. https://doi.org/10.3390/d5030627

    Article  Google Scholar 

  44. Kaakoush NO (2015) Insights into the role of Erysipelotrichaceae in the human host. Front Cell Infect Microbiol 5:84. https://doi.org/10.3389/fcimb.2015.00084

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Keshavarzian A, Green SJ, Engen PA, Voigt RM, Naqib A, Forsyth CB, Mutlu E, Shannon KM (2015) Colonic bacterial composition in Parkinson’s disease. Mov Disord 30(10):1351–1360. https://doi.org/10.1002/mds.26307

    Article  CAS  PubMed  Google Scholar 

  46. Gargari G, Taverniti V, Gardana C, Cremon C, Canducci F, Pagano I, Barbaro MR, Bellacosa L, Castellazzi AM, Valsecchi C, Tagliacarne SC, Bellini M, Bertani L, Gambaccini D, Marchi S, Cicala M, Germana B, Dal Pont E, Vecchi M, Ogliari C, Fiore W, Stanghellini V, Barbara G, Guglielmetti S (2018) Fecal Clostridiales distribution and short-chain fatty acids reflect bowel habits in irritable bowel syndrome. Environ Microbiol. https://doi.org/10.1111/1462-2920.14271

    Article  PubMed  Google Scholar 

  47. Carvalho FA, Koren O, Goodrich JK, Johansson ME, Nalbantoglu I, Aitken JD, Su Y, Chassaing B, Walters WA, Gonzalez A, Clemente JC, Cullender TC, Barnich N, Darfeuille-Michaud A, Vijay-Kumar M, Knight R, Ley RE, Gewirtz AT (2012) Transient inability to manage proteobacteria promotes chronic gut inflammation in TLR5-deficient mice. Cell Host Microbe 12(2):139–152. https://doi.org/10.1016/j.chom.2012.07.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The present study was supported by the Chongqing Yuzhong Nature Science Foundation of China (Grant No. 20160121).

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Authors and Affiliations

  1. School of Public Health and Management, Chongqing Medical University, 1 Yi Xue Yuan Road, Chongqing, 400016, People’s Republic of China

    Feng Lai, Wenjun Xie, Xinrong Liu, Hong Xiao, Jieying Gao, Yan Jia & Qunhua Bai

  2. School of Basic Medicine, Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Rong Jiang

  3. Chongqing Orthopedics Hospital of Traditional Chinese Medicine, Chongqing, 400016, People’s Republic of China

    Yong Tang

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  1. Feng Lai
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Fig. S1 Indexes of α-diversity including Sobs (a) and Simpson (b). (BMP 39361 KB)

11064_2018_2620_MOESM2_ESM.bmp

Fig. S2 Comparisons of the relative abundance of gut microbiota at the order level (a) and the phylum level (b). *P < 0.05, **P < 0.01. Error bars are SD (n= 3). (BMP 39361 KB)

Fig. S3 Relative abundance of Firmicutes (a) and Akkermansia (b). (TIF 225 KB)

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Lai, F., Jiang, R., Xie, W. et al. Intestinal Pathology and Gut Microbiota Alterations in a Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Mouse Model of Parkinson’s Disease. Neurochem Res 43, 1986–1999 (2018). https://doi.org/10.1007/s11064-018-2620-x

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