Advertisement

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

  • Feng Lai
  • Rong Jiang
  • Wenjun Xie
  • Xinrong Liu
  • Yong Tang
  • Hong Xiao
  • Jieying Gao
  • Yan Jia
  • Qunhua Bai
Original Paper

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.

Keywords

Parkinson’s disease MPTP Intestinal pathology Gut microbiota 

Notes

Acknowledgements

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

Compliance with Ethical Standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

11064_2018_2620_MOESM1_ESM.bmp (38.4 mb)
Fig. S1 Indexes of α-diversity including Sobs (a) and Simpson (b). (BMP 39361 KB)
11064_2018_2620_MOESM2_ESM.bmp (38.4 mb)
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)
11064_2018_2620_MOESM3_ESM.tif (225 kb)
Fig. S3 Relative abundance of Firmicutes (a) and Akkermansia (b). (TIF 225 KB)

References

  1. 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 CrossRefPubMedGoogle Scholar
  2. 2.
    Kalia LV, Lang AE (2015) Parkinson’s disease. Lancet 386(9996):896–912.  https://doi.org/10.1016/s0140-6736(14)61393-3 CrossRefPubMedGoogle Scholar
  3. 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 CrossRefPubMedGoogle Scholar
  4. 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 CrossRefPubMedGoogle Scholar
  5. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 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 CrossRefPubMedGoogle Scholar
  7. 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 CrossRefPubMedGoogle Scholar
  8. 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 CrossRefPubMedGoogle Scholar
  9. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  10. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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 CrossRefPubMedGoogle Scholar
  12. 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 CrossRefPubMedGoogle Scholar
  13. 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 PubMedPubMedCentralGoogle Scholar
  14. 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 CrossRefPubMedGoogle Scholar
  15. 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 CrossRefPubMedGoogle Scholar
  16. 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 CrossRefPubMedGoogle Scholar
  17. 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 CrossRefPubMedGoogle Scholar
  18. 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 CrossRefPubMedGoogle Scholar
  19. 19.
    Sawada M, Imamura K, Nagatsu T (2006) Role of cytokines in inflammatory process in Parkinson’s disease. J Neural Transm Suppl 70:373–381CrossRefGoogle Scholar
  20. 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):1–9CrossRefPubMedGoogle Scholar
  21. 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 CrossRefPubMedGoogle Scholar
  22. 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 Google Scholar
  23. 23.
    Nicotra A, Parvez SH (2000) Cell death induced by MPTP, a substrate for monoamine oxidase B. Toxicology 153(1–3):157–166CrossRefPubMedGoogle Scholar
  24. 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):321–326CrossRefPubMedGoogle Scholar
  25. 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 CrossRefPubMedGoogle Scholar
  26. 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 CrossRefPubMedGoogle Scholar
  27. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 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 CrossRefPubMedGoogle Scholar
  29. 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 CrossRefGoogle Scholar
  30. 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 CrossRefPubMedGoogle Scholar
  31. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 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 CrossRefPubMedGoogle Scholar
  33. 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 CrossRefPubMedGoogle Scholar
  34. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  35. 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):6853–6861CrossRefPubMedGoogle Scholar
  36. 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 CrossRefPubMedGoogle Scholar
  37. 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 CrossRefPubMedGoogle Scholar
  38. 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 CrossRefPubMedGoogle Scholar
  39. 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 CrossRefPubMedGoogle Scholar
  40. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 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 CrossRefPubMedGoogle Scholar
  42. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 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 CrossRefGoogle Scholar
  44. 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 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 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 CrossRefPubMedGoogle Scholar
  46. 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 PubMedGoogle Scholar
  47. 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 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Feng Lai
    • 1
  • Rong Jiang
    • 2
  • Wenjun Xie
    • 1
  • Xinrong Liu
    • 1
  • Yong Tang
    • 3
  • Hong Xiao
    • 1
  • Jieying Gao
    • 1
  • Yan Jia
    • 1
  • Qunhua Bai
    • 1
  1. 1.School of Public Health and ManagementChongqing Medical UniversityChongqingPeople’s Republic of China
  2. 2.School of Basic MedicineChongqing Medical UniversityChongqingPeople’s Republic of China
  3. 3.Chongqing Orthopedics Hospital of Traditional Chinese MedicineChongqingPeople’s Republic of China

Personalised recommendations