, Volume 16, Issue 3, pp 741–760 | Cite as

Neuroprotection of Fasting Mimicking Diet on MPTP-Induced Parkinson’s Disease Mice via Gut Microbiota and Metabolites

  • Zhi-Lan Zhou
  • Xue-Bing Jia
  • Meng-Fei Sun
  • Ying-Li Zhu
  • Chen-Meng Qiao
  • Bo-Ping Zhang
  • Li-Ping Zhao
  • Qin Yang
  • Chun Cui
  • Xue Chen
  • Yan-Qin ShenEmail author
Original Article


Parkinson’s disease (PD) is strongly associated with life style, especially dietary habits, which have gained attention as disease modifiers. Here, we report a fasting mimicking diet (FMD), fasting 3 days followed by 4 days of refeeding for three 1-week cycles, which accelerated the retention of motor function and attenuated the loss of dopaminergic neurons in the substantia nigra in 1-methyl-4-phenyl-1,2,3,6-tetrathydropyridine (MPTP)-induced PD mice. Levels of brain-derived neurotrophic factor (BDNF), known to promote the survival of dopaminergic neurons, were increased in PD mice after FMD, suggesting an involvement of BDNF in FMD-mediated neuroprotection. Furthermore, FMD decreased the number of glial cells as well as the release of TNF-α and IL-1β in PD mice, showing that FMD also inhibited neuro-inflammation. 16S and 18S rRNA sequencing of fecal microbiota showed that FMD treatment modulated the shifts in gut microbiota composition, including higher abundance of Firmicutes, Tenericutes, and Opisthokonta and lower abundance of Proteobacteria at the phylum level in PD mice. Gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry revealed that FMD modulated the MPTP-induced lower propionic acid and isobutyric acid, and higher butyric acid and valeric acid and other metabolites. Transplantation of fecal microbiota, from normal mice with FMD treatment to antibiotic-pretreated PD mice increased dopamine levels in the recipient PD mice, suggesting that gut microbiota contributed to the neuroprotection of FMD for PD. These findings demonstrate that FMD can be a new means of preventing and treating PD through promoting a favorable gut microbiota composition and metabolites.

Key Words

Parkinson’s disease fasting mimicking diet gut microbiota metabolites neuro-inflammation BDNF 



This study was supported by National Natural Science Foundation of China (81771384, 81801276), Postgraduate Research & Practice Innovation (KYCX18_1870), Public Health Research Center at Jiangnan University (JUPH201801), and national first-class discipline program of Food Science and Technology (JUFSTR20180101). We sincerely thank Dr. Stanley Li Lin’s careful revision on the manuscript.

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Supplementary material

13311_2019_719_Fig10_ESM.png (581 kb)
Supplementary Fig. 1

Changes of relative abundance of gut microbiota. (a) Relative abundance of gut microbiota changed significantly at the phylum level, based on 16S rRNA sequencing. (b) Relative abundance of gut microbiota changed significantly at the class level, based on 16S rRNA sequencing. (c) Relative abundance of gut microbiota changed significantly at the order level, based on 16S rRNA sequencing. (d) Relative abundance of gut microbiota changed significantly at the family level, based on 16S rRNA sequencing. Statistical comparison by one-way ANOVA with post hoc comparisons of LSD; data represent the means ± SEM; *p < 0.05, **p < 0.01, ***p < 0.001; n = 10 mice per group. (PNG 581 kb)

13311_2019_719_MOESM1_ESM.tif (3.6 mb)
High resolution image (TIF 3650 kb)
13311_2019_719_Fig11_ESM.png (150 kb)
Supplementary Fig. 2

Principal coordinates analysis (PCoA). (a) Principal coordinate analysis based on the Bray-Curtis similarity index of 16S rRNA sequencing. (b) Principal coordinate analysis based on the Bray-Curtis similarity index of 18S rRNA sequencing. (PNG 150 kb)

13311_2019_719_MOESM2_ESM.tif (1.1 mb)
High resolution image (TIF 1091 kb)
13311_2019_719_MOESM3_ESM.pdf (486 kb)
ESM 1 (PDF 486 kb)


  1. 1.
    Poewe W, Seppi K, Tanner CM, et al. Parkinson disease. Nature Reviews Disease Primers 2017; 3: 17013.CrossRefPubMedGoogle Scholar
  2. 2.
    Cacabelos R. Parkinson’s disease: from pathogenesis to pharmacogenomics. International Journal of Molecular Sciences 2017; 183: 551.CrossRefGoogle Scholar
  3. 3.
    Mukherjee A, Biswas A, and Das SK. Gut dysfunction in Parkinson’s disease. World Journal of Gastroenterology 2016; 2225: 5742–5752.CrossRefGoogle Scholar
  4. 4.
    Thomas B and Beal MF. Parkinson’s disease. Hum Mol Genet 2007; 16 Spec No. 2: 183–194.Google Scholar
  5. 5.
    Bousquet M, St-Amour I, Vandal M, et al. High-fat diet exacerbates MPTP-induced dopaminergic degeneration in mice. Neurobiology of Disease 2012; 451: 529–538.CrossRefGoogle Scholar
  6. 6.
    Choi JY, Jang EH, Park CS, and Kang JH. Enhanced susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxicity in high-fat diet-induced obesity. Free Radic Biol Med 2005; 386: 806–816.CrossRefGoogle Scholar
  7. 7.
    Maswood N, Young J, Tilmont E, et al. Caloric restriction increases neurotrophic factor levels and attenuates neurochemical and behavioral deficits in a primate model of Parkinson’s disease. Proc Natl Acad Sci U S A 2004; 10152: 18171–18176.CrossRefGoogle Scholar
  8. 8.
    Duan WZ, Guo ZH, Jiang HY, et al. Dietary restriction normalizes glucose metabolism and BDNF levels, slows disease progression, and increases survival in huntingtin mutant mice. Proc Natl Acad Sci U S A 2003; 1005: 2911–2916.CrossRefGoogle Scholar
  9. 9.
    Choi IY, Piccio L, Childress P, et al. A diet mimicking fasting promotes regeneration and reduces autoimmunity and multiple sclerosis symptoms. Cell Rep 2016; 1510: 2136–2146.CrossRefGoogle Scholar
  10. 10.
    Brandhorst S, Choi IY, Wei M, et al. A periodic diet that mimics fasting promotes multi-system regeneration, enhanced cognitive performance, and healthspan. Cell Metab 2015; 221: 86–99.CrossRefGoogle Scholar
  11. 11.
    Wei M, Brandhorst S, Shelehchi M, et al. Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease. Sci Transl Med 2017; 9377.Google Scholar
  12. 12.
    Cheng CW, Villani V, Buono R, et al. Fasting-mimicking diet promotes Ngn3-driven beta-cell regeneration to reverse diabetes. Cell 2017; 1685: 775–788.Google Scholar
  13. 13.
    Deitch EA, Winterton J, and Berg R. Effect of starvation, malnutrition, and trauma on the gastrointestinal tract flora and bacterial translocation. Arch Surg 1987; 1229: 1019–1024.CrossRefGoogle Scholar
  14. 14.
    Sonoyama K, Fujiwara R, Takemura N, et al. Response of gut microbiota to fasting and hibernation in Syrian hamsters. Appl Environ Microbiol 2009; 7520: 6451–6456.CrossRefGoogle Scholar
  15. 15.
    Li GL, Xie C, Lu SY, et al. Intermittent fasting promotes white adipose browning and decreases obesity by shaping the gut microbiota. Cell Metab 2017; 264: 672–685.CrossRefGoogle Scholar
  16. 16.
    Zarrinpar A, Chaix A, Yooseph S, and Panda S. Diet and feeding pattern affect the diurnal dynamics of the gut microbiome. Cell Metab 2014; 206: 1006–1017.CrossRefGoogle Scholar
  17. 17.
    Zhang LS and Davies SS. Microbial metabolism of dietary components to bioactive metabolites: opportunities for new therapeutic interventions. Genome Med 2016; 8: 46.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Luczynski P, Neufeld KAM, Oriach CS, et al. Growing up in a bubble: using germ-free animals to assess the influence of the gut microbiota on brain and behavior. Int J Neuropsychopharmacol 2016; 198: 1–17.Google Scholar
  19. 19.
    Sampson TR, Debelius JW, Thron T, et al. Gut microbiota regulate motor deficits and neuroinflammation in a model of Parkinson’s disease. Cell 2016; 1676: 1469–1480.Google Scholar
  20. 20.
    Qian Y, Yang X, Xu S, et al. Alteration of the fecal microbiota in Chinese patients with Parkinson’s disease. Brain Behav Immun 2018; 70: 194–202.CrossRefPubMedGoogle Scholar
  21. 21.
    Yang X, Qian Y, Xu S, Song Y, and Xiao Q. Longitudinal analysis of fecal microbiome and pathologic processes in a rotenone induced mice model of Parkinson’s disease. Front Aging Neurosci 2017; 9: 441.CrossRefPubMedGoogle Scholar
  22. 22.
    Torres ERS, Akinyeke T, Stagaman K, et al. Effects of sub-chronic MPTP exposure on behavioral and cognitive performance and the microbiome of wild-type and mGlu8 knockout female and male mice. Front Behav Neurosci 2018; 12: 140.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Clarke TB, Davis KM, Lysenko ES, et al. Recognition of peptidoglycan from the microbiota by Nod1 enhances systemic innate immunity. Nat Med 2010; 162: 228–231.CrossRefGoogle Scholar
  24. 24.
    Schuijt TJ, Lankelma JM, Scicluna BP, et al. The gut microbiota plays a protective role in the host defence against pneumococcal pneumonia. Gut 2016; 654: 575–583.CrossRefGoogle Scholar
  25. 25.
    Chen GY, Shaw MH, Redondo G, and Nunez G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res 2008; 6824: 10060–10067.CrossRefGoogle Scholar
  26. 26.
    Gacias M, Gaspari S, Santos PMG, et al. Microbiota-driven transcriptional changes in prefrontal cortex override genetic differences in social behavior. Elife 2016; 5: e13442.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Ricaurte GA, Langston JW, Delanney LE, et al. Fate of nigrostriatal neurons in young mature mice given 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine: a neurochemical and morphological reassessment. Brain Res 1986; 3761: 117–124.CrossRefGoogle Scholar
  28. 28.
    Kiriyama K, Ohtaki H, Kobayashi N, et al. A nucleoprotein-enriched diet suppresses dopaminergic neuronal cell loss and motor deficit in mice with MPTP-induced Parkinson’s disease. J Mol Neurosci 2015; 553: 803–811.CrossRefGoogle Scholar
  29. 29.
    Ubeda C, Bucci V, Caballero S, et al. Intestinal microbiota containing barnesiella species cures vancomycin-resistant Enterococcus faecium colonization. Infect Immun 2013; 813: 965–973.CrossRefGoogle Scholar
  30. 30.
    Cao Q, Qin LY, Huang F, et al. Amentoflavone protects dopaminergic neurons in MPTP-induced Parkinson's disease model mice through PI3K/Akt and ERK signaling pathways. Toxicol Appl Pharmacol 2017; 319: 80–90.CrossRefPubMedGoogle Scholar
  31. 31.
    Hu M, Li FM, and Wang WD. Vitexin protects dopaminergic neurons in MPTP-induced Parkinson’s disease through PI3K/Akt signaling pathway. Drug Design Development and Therapy 2018; 12: 565–573.CrossRefGoogle Scholar
  32. 32.
    Ahmed M and Ghanem A. Enantioselective nano liquid chromatographic separation of racemic pharmaceuticals: a facile one-pot in situ preparation of lipase-based polymer monoliths in capillary format. Chirality 2014; 2611: 754–763.CrossRefGoogle Scholar
  33. 33.
    Peiffer JA, Spor A, Koren O, et al. Diversity and heritability of the maize rhizosphere microbiome under field conditions. Proc Natl Acad Sci U S A 2013; 11016: 6548–6553.CrossRefGoogle Scholar
  34. 34.
    Baxter NT, Wan JJ, Schubert AM, et al. Intra- and interindividual variations mask interspecies variation in the microbiota of sympatric peromyscus populations. Appl Environ Microbiol 2015; 811: 396–404.CrossRefGoogle Scholar
  35. 35.
    Caporaso JG, Kuczynski J, Stombaugh J, et al. QIIME allows analysis of high-throughput community sequencing data. Nat Methods 2010; 75: 335–336.CrossRefGoogle Scholar
  36. 36.
    Edgar RC. Search and clustering orders of magnitude faster than BLAST. Bioinformatics 2010; 2619: 2460–2461.CrossRefGoogle Scholar
  37. 37.
    DeSantis TZ, Hugenholtz P, Larsen N, et al. Greengenes, a chimera-checked 16S rRNA gene database and workbench compatible with ARB. Appl Environ Microbiol 2006; 727: 5069–5072.CrossRefGoogle Scholar
  38. 38.
    Wang Q, Garrity GM, Tiedje JM, and Cole JR. Naive Bayesian classifier for rapid assignment of rRNA sequences into the new bacterial taxonomy. Appl Environ Microbiol 2007; 7316: 5261–5267.CrossRefGoogle Scholar
  39. 39.
    Garcia-Villalba R, Gimenez-Bastida JA, Garcia-Conesa MT, et al. Alternative method for gas chromatography-mass spectrometry analysis of short-chain fatty acids in faecal samples. J Sep Sci 2012; 3515: 1906–1913.CrossRefGoogle Scholar
  40. 40.
    Zhao L, Zhang F, Ding X, et al. Gut bacteria selectively promoted by dietary fibers alleviate type 2 diabetes. Science 2018; 3596380: 1151–1156.CrossRefGoogle Scholar
  41. 41.
    Xu W, Chen D, Wang N, et al. Development of high-performance chemical isotope labeling LC-MS for profiling the human fecal metabolome. Anal Chem 2015; 872: 829–836.CrossRefGoogle Scholar
  42. 42.
    Palasz E, Bak A, Gasiorowska A, and Niewiadomska G. The role of trophic factors and inflammatory processes in physical activity-induced neuroprotection in Parkinson’s disease. Postepy Hig Med Dosw (Online) 2017; 711: 713–726.Google Scholar
  43. 43.
    Lei E, Vacy K, and Boon WC. Fatty acids and their therapeutic potential in neurological disorders. Neurochem Int 2016; 95: 75–84.CrossRefPubMedGoogle Scholar
  44. 44.
    Anderson G, Noorian AR, Taylor G, et al. Loss of enteric dopaminergic neurons and associated changes in colon motility in an MPTP mouse model of Parkinson’s disease. Exp Neurol 2007; 2071: 4–12.CrossRefGoogle Scholar
  45. 45.
    Natale G, Kastsiushenka O, Fulceri F, et al. MPTP-induced parkinsonism extends to a subclass of TH-positive neurons in the gut. Brain Res 2010; 1355: 195–206.CrossRefPubMedGoogle Scholar
  46. 46.
    Cote M, Drouin-Ouellet J, Cicchetti F, and Soulet D. The critical role of the MyD88-dependent pathway in non-CNS MPTP-mediated toxicity. Brain Behav Immun 2011; 256: 1143–1152.CrossRefGoogle Scholar
  47. 47.
    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 2018; 4310: 1986–1999.CrossRefGoogle Scholar
  48. 48.
    Braak H, de Vos RA, Bohl J, and Del Tredici K. Gastric alpha-synuclein immunoreactive inclusions in Meissner’s and Auerbach’s plexuses in cases staged for Parkinson’s disease-related brain pathology. Neurosci Lett 2006; 3961: 67–72.CrossRefGoogle Scholar
  49. 49.
    Phillips RJ, Walter GC, Wilder SL, Baronowsky EA, and Powley TL. Alpha-synuclein-immunopositive myenteric neurons and vagal preganglionic terminals: autonomic pathway implicated in Parkinson’s disease? Neuroscience 2008; 1533: 733–750.CrossRefGoogle Scholar
  50. 50.
    Scheperjans F, Aho V, Pereira PAB, et al. Gut microbiota are related to Parkinson’s disease and clinical phenotype. Mov Disord 2015; 303: 350–358.CrossRefGoogle Scholar
  51. 51.
    Howells DW, Porritt MJ, Wong JY, et al. Reduced BDNF mRNA expression in the Parkinson’s disease substantia nigra. Exp Neurol 2000; 1661: 127–135.Google Scholar
  52. 52.
    Baquet ZC, Gorski JA, and Jones KR. Early striatal dendrite deficits followed by neuron loss with advanced age in the absence of anterograde cortical brain-derived neurotrophic factor. J Neurosci 2004; 2417: 4250–4258.CrossRefGoogle Scholar
  53. 53.
    Baydyuk M, Nguyen MT, and Xu B. Chronic deprivation of TrkB signaling leads to selective late-onset nigrostriatal dopaminergic degeneration. Exp Neurol 2011; 2281: 118–125.CrossRefGoogle Scholar
  54. 54.
    Bergami M, Santi S, Formaggio E, et al. Uptake and recycling of pro-BDNF for transmitter-induced secretion by cortical astrocytes. J Cell Biol 2008; 1832: 213–221.Google Scholar
  55. 55.
    Coull JA, Beggs S, Boudreau D, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005; 4387070: 1017–1021.CrossRefGoogle Scholar
  56. 56.
    Parkhurst CN, Yang G, Ninan I, et al. Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor. Cell 2013; 1557: 1596–1609.CrossRefGoogle Scholar
  57. 57.
    Elkabes S, DiCicco-Bloom EM, and Black IB. Brain microglia/macrophages express neurotrophins that selectively regulate microglial proliferation and function. J Neurosci 1996; 168: 2508–2521.CrossRefGoogle Scholar
  58. 58.
    Miwa T, Furukawa S, Nakajima K, Furukawa Y, and Kohsaka S. Lipopolysaccharide enhances synthesis of brain-derived neurotrophic factor in cultured rat microglia. J Neurosci Res 1997; 506: 1023–1029.CrossRefGoogle Scholar
  59. 59.
    Knott C, Stern G, Kingsbury A, Welcher AA, and Wilkin GP. Elevated glial brain-derived neurotrophic factor in Parkinson’s diseased nigra. Parkinsonism Relat Disord 2002; 85: 329–341.CrossRefGoogle Scholar
  60. 60.
    Barrientos RM, Sprunger DB, Campeau S, et al. BDNF mRNA expression in rat hippocampus following contextual learning is blocked by intrahippocampal IL-1beta administration. J Neuroimmunol 2004; 1551-2: 119–126.CrossRefGoogle Scholar
  61. 61.
    Tong L, Balazs R, Soiampornkul R, Thangnipon W, and Cotman CW. Interleukin-1 beta impairs brain derived neurotrophic factor-induced signal transduction. Neurobiol Aging 2008; 299: 1380–1393.CrossRefGoogle Scholar
  62. 62.
    Duan W, Guo Z, and Mattson MP. Brain-derived neurotrophic factor mediates an excitoprotective effect of dietary restriction in mice. J Neurochem 2001; 762: 619–626.CrossRefGoogle Scholar
  63. 63.
    Vasconcelos AR, Yshii LM, Viel TA, et al. Intermittent fasting attenuates lipopolysaccharide-induced neuroinflammation and memory impairment. J Neuroinflammation 2014; 11: 85.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Sun MF, Zhu YL, Zhou ZL, et al. 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 2018; 70: 48–60.CrossRefPubMedGoogle Scholar
  65. 65.
    Keshavarzian A, Green SJ, Engen PA, et al. Colonic bacterial composition in Parkinson’s disease. Mov Disord 2015; 3010: 1351–1360.CrossRefGoogle Scholar
  66. 66.
    Jenkins TA, Nguyen JC, Polglaze KE, and Bertrand PP. Influence of tryptophan and serotonin on mood and cognition with a possible role of the gut-brain axis. Nutrients 2016; 81: E56.CrossRefGoogle Scholar
  67. 67.
    O'Mahony SM, Clarke G, Borre YE, Dinan TG, and Cryan JF. Serotonin, tryptophan metabolism and the brain-gut-microbiome axis. Behav Brain Res 2015; 277: 32–48.CrossRefPubMedGoogle Scholar
  68. 68.
    Clarke G, Grenham S, Scully P, et al. The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner. Mol Psychiatry 2013; 186: 666–673.CrossRefGoogle Scholar
  69. 69.
    Westfall S, Lomis N, Kahouli I, et al. Microbiome, probiotics and neurodegenerative diseases: deciphering the gut brain axis. Cell Mol Life Sci 2017; 7420: 3769–3787.CrossRefGoogle Scholar
  70. 70.
    Yamashiro K, Tanaka R, Urabe T, et al. Gut dysbiosis is associated with metabolism and systemic inflammation in patients with ischemic stroke. PLoS One 2017; 122: e0171521.CrossRefGoogle Scholar
  71. 71.
    Unger MM, Spiegel J, Dillmann KU, et al. Short chain fatty acids and gut microbiota differ between patients with Parkinson’s disease and age-matched controls. Parkinsonism Relat Disord 2016; 32: 66–72.CrossRefGoogle Scholar

Copyright information

© The American Society for Experimental NeuroTherapeutics, Inc. 2019

Authors and Affiliations

  1. 1.Public Health Research Center at Jiangnan University, Wuxi Medical SchoolJiangnan UniversityWuxiChina

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