Structural changes of gut microbiota in Parkinson’s disease and its correlation with clinical features

Abstract

The aim of this study was to compare the structure of gut microbiota in Parkinson’s disease (PD) patients and healthy controls; and to explore correlations between gut microbiota and PD clinical features. We analyzed fecal bacterial composition of 24 PD patients and 14 healthy volunteers by using 16S rRNA sequencing. There were significant differences between PD and healthy controls, as well as among different PD stages. The putative cellulose degrading bacteria from the genera Blautia (P=0.018), Faecalibacterium (P=0.048) and Ruminococcus (P=0.019) were significantly decreased in PD compared to healthy controls. The putative pathobionts from the genera Escherichia-Shigella (P=0.038), Streptococcus (P=0.01), Proteus (P=0.022), and Enterococcus (P=0.006) were significantly increased in PD subjects. Correlation analysis indicated that disease severity and PD duration negatively correlated with the putative cellulose degraders, and positively correlated with the putative pathobionts. The results suggest that structural changes of gut microbiota in PD are characterized by the decreases of putative cellulose degraders and the increases of putative pathobionts, which may potentially reduce the production of short chain fatty acids, and produce more endotoxins and neurotoxins; and these changes is potentially associated with the development of PD pathology.

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References

  1. Abell, G.C.J., Cooke, C.M., Bennett, C.N., Conlon, M.A., and McOrist, A.L. (2008). Phylotypes related to Ruminococcus bromii are abundant in the large bowel of humans and increase in response to a diet high in resistant starch. FEMS Microbiol Ecol 66, 505–515.

    CAS  Article  PubMed  Google Scholar 

  2. Adams, J.B., Johansen, L.J., Powell, L.D., Quig, D., and Rubin, R.A. (2011). Gastrointestinal flora and gastrointestinal status in children with autism-comparisons to typical children and correlation with autism severity. BMC Gastroenterol 11, 22.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Agachan, F., Chen, T., Pfeifer, J., Reissman, P., and Wexner, S.D. (1996). A constipation scoring system to simplify evaluation and management of constipated patients. Dis Colon Rectum 39, 681–685.

    CAS  Article  PubMed  Google Scholar 

  4. Bercik, P., Denou, E., Collins, J., Jackson, W., Lu, J., Jury, J., Deng, Y., Blennerhassett, P., Macri, J., McCoy, K.D., Verdu, E.F., and Collins, S.M. (2011). The intestinal microbiota affect central levels of brain-derived neurotropic factor and behavior in mice. Gastroenterology 141, 599–609.e3.

    CAS  Article  PubMed  Google Scholar 

  5. Bolger, A.M., Lohse, M., and Usadel, B. (2014). Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics 30, 2114–2120.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  6. Braak, H., Ghebremedhin, E., Rüb, U., Bratzke, H., and Del Tredici, K. (2004). Stages in the development of Parkinson’s disease-related pathology. Cell Tissue Res 318, 121–134.

    Article  PubMed  Google Scholar 

  7. Braak, H., Rüb, U., Gai, W.P., and 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 (Vienna) 110, 517–536.

    CAS  Article  Google Scholar 

  8. Bridgewater, F.A., Morgan, R.S., Rowson, K.E., and Wright, G.P. (1955). The Neurotoxin of Shigella shigae: morphological and functional lesions produced in the central nervous system of rabbits. Br J Exp Pathol 36, 447–453.

    Google Scholar 

  9. Brugman, S., Klatter, F.A., Visser, J.T.J., Wildeboer-Veloo, A.C.M., Harmsen, H.J.M., Rozing, J., and Bos, N.A. (2006). Antibiotic treatment partially protects against type 1 diabetes in the Bio-Breeding diabetes-prone rat. Is the gut flora involved in the development of type 1 diabetes? Diabetologia 49, 2105–2108.

    CAS  Article  PubMed  Google Scholar 

  10. Cavanagh, J., Howard, J., and Whitby, J. (1956). The neurotoxin of Shigella shigae. A comparative study of the effects produced in various laboratory animals. Br J Exp Pathol 37, 272.

    CAS  PubMed  Google Scholar 

  11. Cersosimo, M.G., Raina, G.B., Pecci, C., Pellene, A., Calandra, C.R., Gutiérrez, C., Micheli, F.E., and Benarroch, E.E. (2013). Gastrointestinal manifestations in Parkinson’s disease: prevalence and occurrence before motor symptoms. J Neurol 260, 1332–1338.

    CAS  Article  PubMed  Google Scholar 

  12. Chaudhuri, K.R., Healy, D.G., and Schapira, A.H. (2006). Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol 5, 235–245.

    Article  PubMed  Google Scholar 

  13. Chen, Y., Yang, F., Lu, H., Wang, B., Chen, Y., Lei, D., Wang, Y., Zhu, B., and Li, L. (2011). Characterization of fecal microbial communities in patients with liver cirrhosis. Hepatology 54, 562–572.

    Article  PubMed  Google Scholar 

  14. Cho, Y., Turner, N.D., Davidson, L.A., Chapkin, R.S., Carroll, R.J., and Lupton, J.R. (2014). Colon cancer cell apoptosis is induced by combined exposure to the n-3 fatty acid docosahexaenoic acid and butyrate through promoter methylation. Exp Biol Med 239, 302–310.

    Article  Google Scholar 

  15. Collins, S.M., and Bercik, P. (2009). The relationship between intestinal microbiota and the central nervous system in normal gastrointestinal function and disease. Gastroenterology 136, 2003–2014.

    Article  PubMed  Google Scholar 

  16. Cryan, J.F., and Dinan, T.G. (2012). Mind-altering microorganisms: the impact of the gut microbiota on brain and behaviour. Nat Rev Neurosci 13, 701–712.

    CAS  Article  PubMed  Google Scholar 

  17. de Lau, L.M., and Breteler, M.M. (2006). Epidemiology of Parkinson’s disease. Lancet Neurol 5, 525–535.

    Article  PubMed  Google Scholar 

  18. Dobbs, R.J., Charlett, A., Dobbs, S.M., Weller, C., A Ibrahim, M.A., Iguodala, O., Smee, C., Plant, J.M., Lawson, A.J., Taylor, D., and Bjarnason, I. (2012). Leukocyte-subset counts in idiopathic parkinsonism provide clues to a pathogenic pathway involving small intestinal bacterial overgrowth. A surveillance study. Gut Pathog 4, 12.

    CAS  Article  PubMed  Google Scholar 

  19. Dobbs, R.J., Charlett, A., Purkiss, A.G., Dobbs, S.M., Weller, C., and Peterson, D.W. (1999). Association of circulating TNF-a and IL-6 with ageing and parkinsonism. Acta Neurol Scand 100, 34–41

    CAS  Article  PubMed  Google Scholar 

  20. Dobbs, S.M., Dobbs, R.J., Weller, C., Charlett, A., Augustin, A., Taylor, D., Ibrahim, M.A.A., and Bjarnason, I. (2016). Peripheral aetiopathogenic drivers and mediators of Parkinson’s disease and co-morbidities: role of gastrointestinal microbiota. J Neurovirol 22, 22–32.

    CAS  Article  PubMed  Google Scholar 

  21. Endimiani, A., Luzzaro, F., Brigante, G., Perilli, M., Lombardi, G., Amicosante, G., Roßsolini, G.M., and Toniolo, A. (2005). Proteus mirabilis bloodstream infections: risk factors and treatment outcome related to the expression of extended-spectrum ß-lactamases. Antimicrob Agents Chemother 49, 2598–2605.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. Erkkilä, A., de Mello, V.D.F., Risérus, U., and Laaksonen, D.E. (2008). Dietary fatty acids and cardiovascular disease: an epidemiological approach. Prog Lipid Res 47, 172–187.

    Article  PubMed  Google Scholar 

  23. Fasano, A., Bove, F., Gabrielli, M., Petracca, M., Zocco, M.A., Ragazzoni, E., Barbaro, F., Piano, C., Fortuna, S., Tortora, A., Di Giacopo, R., Campanale, M., Gigante, G., Lauritano, E.C., Navarra, P., Marconi, S., Gasbarrini, A., and Bentivoglio, A.R. (2013). The role of small intestinal bacterial overgrowth in Parkinson’s disease. Mov Disord 28, 1241–1249.

    CAS  Article  PubMed  Google Scholar 

  24. Fasano, A., Visanji, N.P., Liu, L.W.C., Lang, A.E., and Pfeiffer, R.F. (2015). Gastrointestinal dysfunction in Parkinson’s disease. Lancet Neurol 14, 625–639.

    CAS  Article  PubMed  Google Scholar 

  25. Felice, V.D., Quigley, E.M., Sullivan, A.M., O’Keeffe, G.W., and O’Mahony, S.M. (2016). Microbiota-gut-brain signalling in Parkinson’s disease: implications for non-motor symptoms. Parkinsonism Relat Disord 27, 1–8.

    Article  PubMed  Google Scholar 

  26. Goetz, C.G., Poewe, W., Rascol, O., Sampaio, C., Stebbins, G.T., Counsell, C., Giladi, N., Holloway, R.G., Moore, C.G., Wenning, G.K., Yahr, M.D., Seidl, L., and Seidl, L. (2004). Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations The Movement Disorder Society Task Force on rating scales for Parkinson’s disease. Mov Disord 19, 1020–1028.

    Article  PubMed  Google Scholar 

  27. Hamilton, M. (1959). The assessment of anxiety states by rating. Brit J Med Psychol 32, 50–55.

    CAS  Article  PubMed  Google Scholar 

  28. Hamilton, M. (1960). A rating scale for depression. J Neurol Neurosurg Psychiatry 23, 56–62.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  29. Heetun, Z.S., and Quigley, E.M.M. (2012). Gastroparesis and Parkinson’s disease: a systematic review. Parkinsonism Relat Disord 18, 433–440.

    Article  PubMed  Google Scholar 

  30. Hu, X., Wang, T., and Jin, F. (2016). Alzheimer’s disease and gut microbiota. Sci China Life Sci 59, 1006–1023.

    CAS  Article  PubMed  Google Scholar 

  31. Hughes, A.J., Daniel, S.E., Kilford, L., and Lees, A.J. (1992). Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry 55, 181–184.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Huycke, M.M., Abrams, V., and Moore, D.R. (2002). Enterococcus faecalis produces extracellular superoxide and hydrogen peroxide that damages colonic epithelial cell DNA. Carcinogenesis 23, 529–536.

    CAS  Article  PubMed  Google Scholar 

  33. Jiang, H., Ling, Z., Zhang, Y., Mao, H., Ma, Z., Yin, Y., Wang, W., Tang, W., Tan, Z., Shi, J., Li, L., and Ruan, B. (2015). Altered fecal microbiota composition in patients with major depressive disorder. Brain Behav Immun 48, 186–194.

    Article  PubMed  Google Scholar 

  34. Keshavarzian, A., Green, S.J., Engen, P.A., Voigt, R.M., Naqib, A., Forsyth, C.B., Mutlu, E., and Shannon, K.M. (2015). Colonic bacterial composition in Parkinson’s disease. Mov Disord 30, 1351–1360.

    CAS  Article  PubMed  Google Scholar 

  35. Kozich, J.J., Westcott, S.L., Baxter, N.T., Highlander, S.K., and Schloss, P.D. (2013). Development of a dual-index sequencing strategy and curation pipeline for analyzing amplicon sequence data on the MiSeq Illumina sequencing platform. Appl Environ Microbiol 79, 5112–5120.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  36. Lang, A.E. (2011). A critical appraisal of the premotor symptoms of Parkinson’s disease: potential usefulness in early diagnosis and design of neuroprotective trials. Mov Disord 26, 775–783.

    Article  PubMed  Google Scholar 

  37. Leitch, E.C.M.W., Walker, A.W., Duncan, S.H., Holtrop, G., and Flint, H.J. (2007). Selective colonization of insoluble substrates by human faecal bacteria. Environ Microbiol 9, 667–679.

    Article  PubMed  Google Scholar 

  38. Macpherson, A.J., and Harris, N.L. (2004). Opinion: interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 4, 478–485.

    CAS  Article  PubMed  Google Scholar 

  39. Movement Disorder Society Task Force on Rating Scales for Parkinson’s Disease. (2003). The Unified Parkinson’s Disease Rating Scale (UPDRS): status and recommendations. Mov Disord 18, 738–750.

    Article  Google Scholar 

  40. Mulak, A., and Bonaz, B. (2015). Brain-gut-microbiota axis in Parkinson’s disease. World J Gastroenterol 21, 10609–10620.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Nakano, K., Mizuno, T., Sowa, Y., Orita, T., Yoshino, T., Okuyama, Y., Fujita, T., Ohtani-Fujita, N., Matsukawa, Y., Tokino, T., Yamagishi, H., Oka, T., Nomura, H., and Sakai, T. (1997). Butyrate activates the WAF1/Cip1 gene promoter through Sp1 sites in a p53-negative human colon cancer cell line. J Biol Chem 272, 22199–22206.

    CAS  Article  PubMed  Google Scholar 

  42. Nicholson, J.K., Holmes, E., and Wilson, I.D. (2005). Opinion: gut microorganisms, mammalian metabolism and personalized health care. Nat Rev Micro 3, 431–438.

    CAS  Article  Google Scholar 

  43. Ottman, N., Smidt, H., de Vos, W.M., and Belzer, C. (2012). The function of our microbiota: who is out there and what do they do? Front Cell Inf Microbio 2, 104.

    Article  Google Scholar 

  44. Parracho, H.M.R.T., Bingham, M.O., Gibson, G.R., and McCartney, A.L. (2005). Differences between the gut microflora of children with autistic spectrum disorders and that of healthy children. J Med Microbiol 54, 987–991.

    Article  PubMed  Google Scholar 

  45. Pfeiffer, R.F. (2011). Gastrointestinal dysfunction in Parkinson’s disease. Parkinsonism Relat Disord 17, 10–15.

    Article  PubMed  Google Scholar 

  46. Pruesse, E., Quast, C., Knittel, K., Fuchs, B.M., Ludwig, W., Peplies, J., and Glöckner, F.O. (2007). SILVA: a comprehensive online resource for quality checked and aligned ribosomal RNA sequence data compatible with ARB. Nucleic Acids Res 35, 7188–7196.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Qin, N., Yang, F., Li, A., Prifti, E., Chen, Y., Shao, L., Guo, J., Le Chatelier, E., Yao, J., Wu, L., Zhou, J., Ni, S., Liu, L., Pons, N., Batto, J.M., Kennedy, S.P., Leonard, P., Yuan, C., Ding, W., Chen, Y., Hu, X., Zheng, B., Qian, G., Xu, W., Ehrlich, S.D., Zheng, S., and Li, L. (2014). Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64.

    CAS  Article  PubMed  Google Scholar 

  48. Rayner, C.K., and Horowitz, M. (2013). Physiology of the ageing gut. Curr Opin Clin Nutr Metab Care 16, 33–38.

    Article  PubMed  Google Scholar 

  49. Riordan, S.M., and Williams, R. (2006). The intestinal flora and bacterial infection in cirrhosis. J Hepatol 45, 744–757.

    Article  PubMed  Google Scholar 

  50. Schaffer, J.N., and Pearson, M.M. (2015). Proteus mirabilis and Urinary Tract Infections. Microbiol Spectr in press doi: 10.1128/microbiolspec.UTI-0017-2013.

  51. Scheperjans, F., Aho, V., Pereira, P.A.B., Koskinen, K., Paulin, L., Pekkonen, E., Haapaniemi, E., Kaakkola, S., Eerola-Rautio, J., Pohja, M., Kinnunen, E., Murros, K., and Auvinen, P. (2015). Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord 30, 350–358.

    Article  PubMed  Google Scholar 

  52. Scher, J.U., Sczesnak, A., Longman, R.S., Segata, N., Ubeda, C., Bielski, C., Rostron, T., Cerundolo, V., Pamer, E.G., Abramson, S.B., Huttenhower, C., and Littman, D.R. (2013). Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2, e01202.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Schloss, P.D., Westcott, S.L., Ryabin, T., Hall, J.R., Hartmann, M., Hollister, E.B., Lesniewski, R.A., Oakley, B.B., Parks, D.H., Robinson, C.J., Sahl, J.W., Stres, B., Thallinger, G.G., Van Horn, D.J., and Weber, C.F. (2009). Introducing mothur: open-source, platform-independent, community-supported software for describing and comparing microbial communities. Appl Environ Microbiol 75, 7537–7541.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Sjögren, Y.M., Jenmalm, M.C., Böttcher, M.F., Björkstén, B., and Sverremark-Ekström, E. (2009). Altered early infant gut microbiota in children developing allergy up to 5 years of age. Clin Exp Allergy 39, 518–526.

    Article  PubMed  Google Scholar 

  55. Takahashi, K., Nishida, A., Fujimoto, T., Fujii, M., Shioya, M., Imaeda, H., Inatomi, O., Bamba, S., Sugimoto, M., and Andoh, A. (2016). Reduced abundance of butyrate-producing bacteria species in the fecal microbial community in Crohn’s disease. Digestion 93, 59–65.

    CAS  Article  PubMed  Google Scholar 

  56. Tan, A.H., Mahadeva, S., Thalha, A.M., Gibson, P.R., Kiew, C.K., Yeat, C.M., Ng, S.W., Ang, S.P., Chow, S.K., Tan, C.T., Yong, H.S., Marras, C., Fox, S.H., and Lim, S.Y. (2014). Small intestinal bacterial overgrowth in Parkinson’s disease. Parkinsonism Relat Disord 20, 535–540.

    Article  PubMed  Google Scholar 

  57. Topping, D.L., and Clifton, P.M. (2001). Short-chain fatty acids and human colonic function: roles of resistant starch and nonstarch polysaccharides. Physiol Rev 81, 1031-1064.

    CAS  Article  PubMed  Google Scholar 

  58. Vinolo, M.A.R., Rodrigues, H.G., Nachbar, R.T., and Curi, R. (2011). Regulation of inflammation by short chain fatty acids. Nutrients 3, 858–876.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. Walker, A.W., Ince, J., Duncan, S.H., Webster, L.M., Holtrop, G., Ze, X., Brown, D., Stares, M.D., Scott, P., Bergerat, A., Louis, P., McIntosh, F., Johnstone, A.M., Lobley, G.E., Parkhill, J., and Flint, H.J. (2011). Dominant and diet-responsive groups of bacteria within the human colonic microbiota. ISME J 5, 220–230.

    CAS  Article  PubMed  Google Scholar 

  60. Wang, R.F., Cao, W.W., and Cerniglia, C.E. (1997). PCR detection of Ruminococcus spp. in human and animal faecal samples. Mol Cell Probes 11, 259–265.

    CAS  Article  PubMed  Google Scholar 

  61. Wang, T., Cai, G., Qiu, Y., Fei, N., Zhang, M., Pang, X., Jia, W., Cai, S., and Zhao, L. (2012). Structural segregation of gut microbiota between colorectal cancer patients and healthy volunteers. ISME J 6, 320–329.

    CAS  Article  PubMed  Google Scholar 

  62. White, J.R., Nagarajan, N., and Pop, M. (2009). Statistical methods for detecting differentially abundant features in clinical metagenomic samples. PLoS Comput Biol 5, e1000352.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by Future Life Sciences International Ltd. (NSBJ01032014, http://flsi.jp/).

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Correspondence to Feng Jin or Bin Qin.

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Li, W., Wu, X., Hu, X. et al. Structural changes of gut microbiota in Parkinson’s disease and its correlation with clinical features. Sci. China Life Sci. 60, 1223–1233 (2017). https://doi.org/10.1007/s11427-016-9001-4

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Keywords

  • microbiome
  • α-synuclein
  • gastrointestinal dysfunction
  • gut-brain-axis
  • 16S rRNA sequencing
  • short chain fatty acids