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. 2019 Jul;16(3):741-760.
doi: 10.1007/s13311-019-00719-2.

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

Zhi-Lan Zhou  1 , Xue-Bing Jia  1 , Meng-Fei Sun  1 , Ying-Li Zhu  1 , Chen-Meng Qiao  1 , Bo-Ping Zhang  1 , Li-Ping Zhao  1 , Qin Yang  1 , Chun Cui  1 , Xue Chen  1 , Yan-Qin Shen  2
Affiliations

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

Zhi-Lan Zhou et al. Neurotherapeutics. 2019 Jul.

Abstract

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.

Keywords: BDNF; Parkinson’s disease; fasting mimicking diet; gut microbiota; metabolites; neuro-inflammation.

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Figures

Fig. 1
Fig. 1
FMD treatment retains motor function in PD mice without an overall reduction in calorie intake. (a) Timeline for the experimental procedure, including FMD, MPTP administration, and tissue collection. (b) Body weight changes. NS-AL group (n = 17), NS-FMD group (n = 15), MPTP-AL group (n = 18), MPTP-FMD group (n = 16). (c) Average food intake in per cycle, n = 13 mice per group. (d) Pole descent test: time taken represents degree of bradykinesia, F3,59 = 48.325, p < 0.001. NS-AL group (n = 16), NS-FMD group (n = 15), MPTP-AL group (n = 18), MPTP-FMD group (n = 14). (e) Traction test: suspension reflex score for evaluation of muscle strength and equilibrium, F3,62 = 33.929, p < 0.001. NS-AL group (n = 17), NS-FMD group (n = 15), MPTP-AL group (n = 18), MPTP-FMD group (n = 16). Statistical comparison by one-way ANOVA with post hoc comparisons of LSD; data represent the means ± SEM; ***p < 0.001
Fig. 2
Fig. 2
FMD treatment of PD mice attenuates MPTP-induced reduction of brain neurotransmitters. (a) DA concentration in the mouse striatum, F3,37 = 18.462, p < 0.001. (b) 5-HT concentration in the mouse striatum, F3,37 = 4.420, p = 0.009. (c, d) DA turnover in the mouse striatum. The ratio of DOPAC/DA (c) and HVA/DA (d) represents the degree of DA turnover, F3,37 = 12.792, p < 0.001 and F3,37 = 9.221, p < 0.001, respectively. (e) 5-HT turnover in the mouse striatum. The ratio of 5-HIAA/5-HT represents the degree of 5-HT turnover, F3,37 = 3.497, p = 0.025. 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. NS-AL group (n = 11), n = 10 mice in the other three groups
Fig. 3
Fig. 3
FMD treatment of PD mice prevents the MPTP-induced loss in brain dopaminergic neurons and reduction of TH expression. (a) Representative immunofluorescence staining for TH and NeuN in the right and left SN respectively. Scale bar is 100 μm. (b) Quantitative analysis of the number of TH-positive cells in the left SN, F3,12 = 34.100, p < 0.001, n = 4 mice per group. (c) Quantitative analysis of the number of TH-positive cells in the right SN, F3,12 = 51.657, p < 0.001, n = 4 mice per group. (d) Quantitative analysis of the number of NeuN-positive cells in the left SN, F3,12 = 32.374, p < 0.001, n = 4 mice per group. (e) Quantitative analysis of the number of NeuN-positive cells in the right SN, F3,12 = 38.919, p < 0.001, n = 4 mice per group. (f) Representative western blot of striatal TH expression. (g) Band intensity was quantified with the ImageJ software and quantitative data for TH following normalization to GAPDH, F3,24 = 16.732, p < 0.001, n = 7 mice per group. Statistical comparison by one-way ANOVA with post hoc comparisons of LSD; data represent the means ± SEM; **p < 0.01, ***p < 0.001
Fig. 4
Fig. 4
FMD alleviates MPTP-induced neuro-inflammation by retaining BDNF levels. (a) Double immunofluorescence staining for TH (green) and GFAP (red) in the SN. Scale bar is 100 μm. (b) Quantitative analysis of the number of GFAP positive cells in each group, F3,15 = 18.574, p < 0.001. NS-AL group (n = 6), NS-FMD group (n = 5), MPTP-AL group (n = 4), and MPTP-FMD group (n = 4). (c) Double immunofluorescence staining of TH (green) and Iba-1 (red) in the SN. Scale bar is 100 μm. (d) Quantitative analysis of the number of microglia in each group, F3,19 = 21.832, p < 0.001. NS-FMD group (n = 5), n = 6 mice in the other three groups. (e) Representative western blot of striatal BDNF expression. (f) Band intensity was quantified with the ImageJ software and quantitative data for TH following normalization to GAPDH, F3,24 = 7.375, p = 0.001, n = 7 mice per group. (g) ELISA for striatal TNF-α expression, F3,28 = 6.316, p = 0.002, n = 8 mice per group. (h) ELISA for striatal IL-1β expression, F3,20 = 13.529, p < 0.001, n = 6 mice per group. 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
Fig. 5
Fig. 5
FMD modifies the dysbiosis of gut microbiota induced by MPTP based on 16S rRNA sequencing. (a–c) Analysis of alpha diversity-based, 16S rRNA sequencing-predicted gut microbiota richness by the Chao1 index (a), diversity by the Shannon index (b) and the number of OTUs by observed_otus (c). (d) Comparison of the fecal microbiota structures and distribution at the phylum-based 16S rRNA sequencing level. (e) Heatmap based on the Bray–Curtis distance analysis of 16S rRNA showing relative abundance of gut microbiota at the phylum level. (f) Relative abundance of gut microbiota changed significantly at the genus level, based on 16S rRNA sequencing. NA = NS-AL group; NF = NS-FMD group; MA = MPTP-AL group; MF = MPTP-FMD group. n = 10 mice per group
Fig. 6
Fig. 6
FMD modifies the dysbiosis of gut microbiota induced by MPTP based on 18S rRNA sequencing. (a) Analysis of alpha diversity based on 18S rRNA sequencing-predicted gut microbiota richness by the Chao1 index. (b) Comparison of fecal microbiota structures and distribution at the phylum level, based on 18S rRNA sequencing. (c) Heatmap based on the Bray–Curtis distance analysis of 18S rRNA showing relative abundance of gut microbiota at the phylum level. (d) Relative abundance of gut microbiota changed significantly based on 18S rRNA sequencing. NA = NS-AL group; NF = NS-FMD group; MA = MPTP-AL group; MF = MPTP-FMD group. n = 10 mice per group
Fig. 7
Fig. 7
Gut microbiota contribute to FMD-induced neuroprotection in PD. (a) Experimental scheme of antibiotic cocktail treatment and fecal microbiota transplantation. (b, c) DA (b) and 5-HT (c) concentrations in the striatum of mice with transplanting different microbiota following pretreatment with antibiotic cocktails, F3,28 = 4.356, p < 0.001 and F3,28 = 5.917, p = 0.003, respectively, n = 8 mice per group. 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
Fig. 8
Fig. 8
Fecal SCFAs alterations in mice. (a) Concentration of fecal propionic acid, F3,45 = 3.055, p = 0.038. (b) Concentration of fecal isobutyric acid, F3,45 = 3.089, p = 0.036. (c) Concentration of fecal butyric acid, F3,45 = 3.038, p = 0.049. (d) Concentration of fecal valeric acid, F3,45 = 3.072, p = 0.037. (e) Concentration of fecal acetic acid, F3,45 = 50.632, p < 0.001. (f) Concentration of fecal isovaleric acid, F3,45 = 0.952, p = 0.424. 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. NS-AL group (n = 12), NS-FMD group (n = 14), MPTP-AL group (n = 11), MPTP-FMD group (n = 12)
None
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